Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 738235 10.3389/fphar.2021.738235 Pharmacology Review Molecular Basis of Prostate Cancer and Natural Products as Potential Chemotherapeutic and Chemopreventive Agents Bai et al. Natural Products for Prostate Cancer Bai Bingke 1 † Chen Qianbo 2 † Jing Rui 1 † He Xuhui 1 Wang Hongrui 1 Ban Yanfei 1 Ye Qi 3 * Xu Weiheng 4 * Zheng Chengjian 1 * Department of Chinese Medicine Authentication, School of Pharmacy, Second Military Medical University, Shanghai, China Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China Department of Biological Science, College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, China Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China

Edited by: Wei Peng, Chengdu University of Traditional Chinese Medicine, China

Reviewed by: Tao Guo, Henan University of Traditional Chinese Medicine, China

Loh Teng Hern Tan, Monash University Malaysia, Malaysia

 *Correspondence: Qi Ye, qipharm@126.com; Weiheng Xu, xuweiheng7114@163.com; Chengjian Zheng, cjzheng1984@126.com

These authors have contributed equally to this work

This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

 23 09 2021 2021 12 738235 08 07 2021 06 09 2021 Copyright © 2021 Bai, Chen, Jing, He, Wang, Ban, Ye, Xu and Zheng. 2021 Bai, Chen, Jing, He, Wang, Ban, Ye, Xu and Zheng

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Prostate cancer is the second most common malignant cancer in males. It involves a complex process driven by diverse molecular pathways that closely related to the survival, apoptosis, metabolic and metastatic characteristics of aggressive cancer. Prostate cancer can be categorized into androgen dependent prostate cancer and castration-resistant prostate cancer and cure remains elusive due to the developed resistance of the disease. Natural compounds represent an extraordinary resource of structural scaffolds with high diversity that can offer promising chemical agents for making prostate cancer less devastating and curable. Herein, those natural compounds of different origins and structures with potential cytotoxicity and/or in vivo anti-tumor activities against prostate cancer are critically reviewed and summarized according to the cellular signaling pathways they interfere. Moreover, the anti-prostate cancer efficacy of many nutrients, medicinal plant extracts and Chinese medical formulations were presented, and the future prospects for the application of these compounds and extracts were discussed. Although the failure of conventional chemotherapy as well as involved serious side effects makes natural products ideal candidates for the treatment of prostate cancer, more investigations of preclinical and even clinical studies are necessary to make use of these medical substances reasonably. Therefore, the elucidation of structure-activity relationship and precise mechanism of action, identification of novel potential molecular targets, and optimization of drug combination are essential in natural medicine research and development.

 prostate cancer natural compounds apoptosis androgen receptor mechanism Introduction

It is nowadays evident that prostate cancer (PCa) is recognized as the second most common cancer and the fifth cause of cancer death in males (Torre et al., 2015)Initially, the usual therapy for prostate cancer is prostatectomy or radiation, which aims to remove or kill the malignant cells that have not spread or metastasized (Feldman and Feldman, 2001). However, numerous patients cannot be cured thoroughly by this treatment, and then followed by cancer recurrence and/or metastasis. The majority of prostate cancer growth is androgen dependent. Androgen deprivation therapy (ADT) such as surgery or gonadotropin-releasing hormone (GnRH) analog treatment, is the main therapeutic and dramatically effective intervention for the treatment of androgen dependent prostate cancer (ADPC) in putting patients with tumors in remission, as documented by the work on castration of Huggins, who was awarded the Nobel prize in 1966 (Huggins, 1978). Nevertheless, after this therapy, most of these prostate cancer patients gradually become androgen independent, go on to progress, metastasize and resist to ADT within 13–24 months accompanied by increased levels of prostate-specific antigen (PSA). Siegel et al. reported that failure of ADT is responsible for the ∼27,000 metastatic prostate cancer deaths in the United States annually (Siegel et al., 2017). This stage of prostate cancer is called castration-resistant prostate cancer (CRPC), which has poor prognosis (Small et al., 2004). At present, there is no effective therapy for CRPC besides docetaxel, which has been demonstrated to prolong overall survival in this patient population. However, the efficacy of docetaxel is not satisfactory and there are many severe adverse effects such as anemia, neutropenia, diarrhea, and sensory neuropathy. Although, therapeutic options have expanded rapidly since 2011, including AR inhibitors (enzalutamide, abiraterone), immunotherapy (sipuleucel-T), bone seeking radionuclides (radium-223), and second-line chemotherapy (cabazitaxel), all of these agents or interventions only have shown a median survival benefit of 2–5 months (Ritch and Cookson, 2016). So searching for more effective anti-prostate cancer drugs, especially with high efficacy and low toxicity, remains an urgent problem that needs to be resolved. Natural compounds represent an irreplaceable resource of structural scaffolds that can offer chemical agents for making prostate cancer less devastating and curable. In recent years, many natural products and extracts have been scientifically investigated in vitro and/or in vivo and proved as potential anti-prostate cancer agents, which are currently scattered across various publications. So a systematic summary and knowledge of future prospects are necessary to facilitate further chemical and pharmacological studies for anti-prostate cancer agents.

Herein, we reviewed the detailed molecular causes of prostate cancer and critically summarized the natural compounds (or extracts and Chinese herb preparations) that have been reported to inhibit prostate cancer cells proliferation/tumor growth, induce prostate cancer cells apoptosis or exhibit effects on specific signaling pathways involved in prostate cancer in vivo and in vitro. In addition, we also provided possible novel targets for screening natural compounds (or extracts or Chinese herb preparations) with anti-prostate cancer activity and discuss the future prospects for the application of these compounds and extracts and the novel available approaches and technological improvements that should be explored to treat prostate cancer.

 Overview of the Molecular Basis of Prostate Cancer Molecular Basis of Androgen Dependent Prostate Cancer

Androgens, principally testosterone (T) and dihydrotestosterone (DHT), are synthesized from cholesterol as the initial 27-carbon substrate via multiple enzymatic steps (Wadosky and Koochekpour, 2016). As a member of the ligand-activated nuclear hormone receptors superfamily, androgen receptor (AR) is a modular protein with four functional domains: an N-terminal regulatory domain (NTD), a DNA-binding domain (DBD), a small hinge region (H) and a ligand-binding domain (LBD) (Ho and Dehm, 2017). Upon binding to androgens, AR undergoes a conformational change, leading to nuclear translocation, phosphorylation, homodimer, and interaction with DNA (Li and Al-Azzawi, 2009). Subsequently, AR dimer binds to androgen-response elements (AREs), recruits essential co-factors and regulates the expression of androgen-regulated genes (Ho and Dehm, 2017).

The development and maintenance of the prostate is inseparable from androgen acting through the AR. Since Huggins and Hodges first demonstrated the responsiveness of prostate cancer to androgen deprivation, it has been clear that prostate cancer is dependent on androgen and AR activation for growth and survival (Huggins and Hodges, 1941). From then, hundreds of studies have demonstrated that androgen withdrawal results in initial regression of essentially all prostate cancers, albeit for a finite period, with the ultimate development of castration-resistant disease. Androgen deprivation therapy, via either orchidectomy or use of a gonadotropin-releasing hormone (GnRH) agonist has become the cornerstone of therapy in the treatment of prostate cancers. Newer agents, such as abiraterone, which block androgen synthetic pathways, have added clinical benefit in disseminated disease, demonstrating that even in “castration resistant disease” androgens may still be supporting prostate cancer growth (Morgentaler, 2009). These data support the notion that prostate cancer, in most cases, is a hormone (androgen) sensitive disease.

 Overview of the Mechanisms of Castration-Resistant Prostate Cancer

Historically, there are much debate about the mechanisms of castration resistance, which are mainly summarized as the following by recent studies: canonical AR signaling, relying on AR nuclear translocation and AR-DNA binding, and non-nuclear AR signaling which requires neither AR nuclear translocation nor AR-DNA binding(Qin and Bin, 2019; Pisano et al., 2021).

Canonical AR Signaling

The potential mechanisms of canonical AR signaling that lead to CRPC can be categorized into three parts. 1) common alterations in AR, which can lead to AR increase its sensitivity to very low levels of androgens or constitutive activation of AR signaling; 2) AR activation by androgens converted from adrenalandrogens or synthesized intratumorally via the de novo route; 3) alterations in cofactors of the AR pathway (Figure 1 ).

Canonical AR in castration-resistant prostate cancer. Common alterations in AR, including AR amplification or overexpression, AR mutations and truncated AR lacking ligand-binding domains (ARΔLBD), can increase its sensitivity to very low levels of androgens or lead to constitutive activation of AR signaling. There are two possible ways for the initial substrates to convert to intratumoral DHT in CRPC. The first way is that androgens are synthesized intratumorally via the de novo route and the second is that androgens are converted from adrenal androgens. Genomic and transcriptomic alterations in AR pathway coregulators are also associated with resistance to AR-targeted therapies in CRPC.

 Common Alterations in <italic>AR</italic>

One possible mechanism by which the prostate cancer becomes resistant to androgen deprivation therapy is alterations in AR, including AR amplification or overexpression, AR mutations and truncated AR lacking ligand-binding domains (ARΔLBD). Thus, these changes in AR increase its sensitivity to very low levels of androgens or lead to constitutive activation of AR signaling. Strictly speaking, this mechanism of prostate cancers is not androgen-independent and the responses still depend on AR and androgen.

<italic>AR</italic> Amplification or Overexpression

Despite low circulating androgens in the CRPC patients, one potential mechanism that would allow tumor cell proliferation is by promoting the expression of the AR itself, which increases ligand-occupied receptor content (Feldman and Feldman, 2001). Plenty of studies have shown that approximately 50% of tumors that become castration resistant after ADT have amplified the AR gene, the most frequent genetic alteration reported for CRPC tumors, whereas none of the untreated primary tumors before androgen ablation had an AR gene amplification (Robinson et al., 2015; Djusberg et al., 2017).

Numerous studies provide the simplest explanation of how increased androgen receptor expression leads to resistance to anti-androgen therapy. According to one study, a three-to-five-fold increase in receptor levels could compensate for low ligand levels and restore androgen receptor signaling in xenotransplantation models. (Chen et al., 2004). Although tumors with AR amplification have increased levels of AR, the signal for cell proliferation presumably continues to require androgen (Visakorpi et al., 1995). Maybe this can explain why tumors with castration resistance have increased sensitivity to androgens in a low androgen environment.

 <italic>AR</italic> Mutations

In CRPC, the frequency of AR mutations in pre-treated tumors is 5–30% (Grasso et al., 2012; Robinson et al., 2015; Kumar et al., 2016). Most mutations identified in CRPC were located in the AR-LBD. These alterations could facilitate AR signaling in CRPC by offering: 1) ligand facilitation, thereby inducing AR activation even in the presence of low or absent levels of androgens and 2) agonist properties to AR antagonists (Coutinho et al., 2016). In addition, mutations can also occur in the AR-NTD that account for about a third of all mutations described in AR. And mutations can usually cause alterations that contribute to AR transactivation, such as facilitated recruitment of co-factors and other components of the transcriptional machinery, promoted N/C interaction, increased response to DHT activation and enhanced protein stability and nuclear retention (Network C. G. A., 2015; Coutinho et al., 2016).

 Truncated <italic>AR</italic> Lacking Ligand-Binding Domains (<italic>AR</italic>ΔLBD)

Latest RNA sequencing data from big data sets, strongly suggests that constitutively active ARΔLBD may play a role in 40–50% of patients with CRPC (Robinson et al., 2015). Compared with hormone naïve PCa, ARΔLBDs are frequently upregulated in CRPC, and may serve as an adaptive response to therapies targeting the androgen/AR-signaling axis (Guo et al., 2009; Li et al., 2013). The recent genomic data on unique exon junctions reveals that at least 12 distinct AR-V mRNA species are detectable in primary PCa and 23 in CRPC (Abeshouse et al., 2015). However, among these variants, AR-V3/AR-V7 appears to be one of the most abundantly and ubiquitously expressed isoforms in our screening of a panel of human prostate cancer cell lines and tissues (Guo et al., 2009; Schweizer and Plymate, 2016). In addition, nonsense mutations leading to premature chain termination (Q641X, formerly Q640X) as well as enzymatic cleavage (tr-AR) were also shown to induce AR△LBDs (Haile and Sadar, 2011). F. Zengerling et al. reported that inhibition of IGF-1R resulted in a down-regulation of AR, Q641X and AR-V7 signaling in PCa cells (Zengerling et al., 2016), which suggests that IGF-1/IGF-1R axis is a modulator of the AR△LBD signaling, providing a rationale by targeting growth factor receptor for CRPC treatment.

 AR Activation by DHT Synthesized Intratumorally via the <italic>de novo</italic> Route or Converted From Adrenal Androgens

There are two possible ways for the initial substrates to convert to intratumoral DHT in CRPC. The first way is that androgens are synthesized intratumorally via the de novo route and the second is that androgens are converted from adrenal androgens.

DHT Intratumorally via the <italic>de novo</italic> Route

The use of cholesterol for de novo steroidogenesis requires the components of the steroidogenic machinery present in the adrenals and gonads, including steroidogenic acute regulatory proteins, CYP11A1 and CYP17A1 (Miller and Auchus, 2011), which may play important roles in prostate cancer (Locke et al., 2008). Comparisons between primary prostate cancer and CRPC demonstrate that the transcription levels of these proteins are upregulated in CRPC (Montgomery et al., 2008) and CYP17A1 protein is detectable in a subset of metastatic CRPC cases (Efstathiou et al., 2012). In contrast to steroidogenesis in the adrenals and gonads, CRPC expresses steroid-5α-reductase (SRD5A1) with obvious 5α-reductase activity (Chang et al., 2011). One of the functions of robust SRD5A enzyme activity is that any de novo steroidogenesis would likely occur through the back door pathway that bypasses the requirement for T and involves 5-reduction of a 21-carbon steroid (progesterone or 17α-hydroxyprogesterone) instead of a 19-carbon androgen (Shaw et al., 2000; Auchus, 2004). Although this biochemical pathway may be engaged in CRPC, the relatively lengthy eight enzymatic steps required for conversion from cholesterol to DHT, the abundance of adrenal precursors present in serum, and the much closer pathway proximity of adrenal precursors to DHT, together suggest that adrenal precursors serve as the major substrate pool.

 DHT Converted From Adrenal Androgens

There are two possible pathways from adrenal precursor steroids to DHT (Luu-The et al., 2008; Chang and Sharifi, 2012). The canonical adrenal pathway is the route that results in T synthesis as the penultimate metabolite, which undergoes 5-reduction to DHT (Scher and Sawyers, 2005; Ryan and Tindall, 2011; Hofland et al., 2012; Stein et al., 2012). This pathway is probably favored in the field because of the general notion that T must be the precursor to DHT and T is frequently detectable at concentrations greater than DHT in CRPC, as occurs with gonadal androgen physiology (Titus et al., 2005; Montgomery et al., 2008). In this pathway, DHEA is converted by 3β-hydroxysteroid dehydrogenase (3βHSD) to androstenedione (AD), which is then 17-keto reduced by aldo-keto reductase 1C3 (AKR1C3) or 17βHSD3 to T, the immediate precursor to DHT. The second possible pathway is that AD, like T, a 3-keto, △4-steroid, is also a potential substrate for SRD5A (Tomkins, 1957). AD is reduced to 5α-androstanedione (5α-dione), which then becomes the immediate precursor to DHT. The 5α-dione pathway is the major pathway for the synthesis of DHT in CRPC (Chang et al., 2011).

 Alterations in Cofactors of the AR Pathway

Resistance to AR-targeted therapies in CRPC was also associated with genomic and transcriptomic alterations in coregulators of the AR pathway. Expression of 50 of the ∼200 AR-associated coregulators is aberrant in clinical CRPC specimens (Liu et al., 2017). For example, a higher frequency of mutations in FOXA1, the gene encoding a pioneer factor that facilitates AR chromatin binding and transcriptional activation, was found in CRPC (12%) than in primary prostate cancer (4%) (Watson et al., 2013; Abeshouse et al., 2015). In addition, as one class of coregulators, steroid receptor coactivators (SRC-1, SRC-2 and SRC-3) play a key role in facilitating aberrant AR signaling in CRPC e. There have been studies reported that all 3 SRCs is elevated in CRPC (Taylor et al., 2010; Grasso et al., 2012; Abeshouse et al., 2015; Beltran et al., 2016; Bernemann et al., 2016). GATA2, another AR pioneer factor in the AR signaling axis, is aberrant expressed in CRPC and associated with poor outcome (He et al., 2014; Yan et al., 2014). Gupta et al. detected genomic copy number changes of circulating tumor cells from 16 patients with CRPC resistant to abiraterone or enzalutamide and revealed that multiple genes encoding AR coregulators had copy number alterations, including copy number gains BRD4 (43.75%) (Gupta et al., 2017). Moreover, changes of AR corepressors also play a key role in CRPC. For example, loss of activity of the key nuclear receptor corepressors NCOR1 and NCOR2, is prevalent in CRPC due to mutation and/or deletion (Grasso et al., 2012; Abeshouse et al., 2015; Kumar et al., 2016).

 Non-nuclear AR Signaling

Trafficking from the nucleus into the cytoplasm, AR may have unexpected consequences because AR has known functions in the cytoplasm, which is called non-genomic signaling (Foradori et al., 2008). One of the main characteristics of non-nuclear signaling is its rapidity with which it occurs. When steroid receptors stay in the cytosol, they can undergo several protein–protein interactions within seconds to minutes after steroid stimulation, which activates a variety of signaling pathways to promote the development of CRPC (Figure 2).

Non-nuclear AR signaling in castration-resistant prostate cancer. Cytokines, interleukins and the growth factors secreted by the prostate cancer cells activate various signaling cascades like PI3K/AKT, Src, MAPKs and JAK/STAT3 pathways involved in castration-resistant prostate cancer, leading to cell proliferation, survival and tumor metastasis. Intracellular Ca2+ centration can be modulated through Calcium channel. This increase in intracellular Ca2+ can lead to activation of PKC and filamin A, ultimately influencing gene transcription through phosphorylation. TRPM4 is also activated by a rise in intracellular Ca2+ in prostate cancer cells. Upon activation, a Na+ influx via TRPM4 depolarizes the membrane potential, which decreases the driving force for Ca2+, and thus contributes to migration of androgen-insensitive prostate cancer cells. There are other genomic alterations in castration-resistant prostate cancer, including PTEN mutation, SPOP mutation and TMPRSS2-ERG rearrangement.

 PI3K/AKT Signaling Pathway

The PI3K/AKT pathway is one of the most frequently activated signal transduction pathways in human cancer, including prostate cancer(Hoxhaj and Manning, 2020; Park et al., 2018; Braglia et al., 2020). Alterations of the PI3K/AKT pathway, including altered expression, mutation, and copy number alterations, have been reported in 42% of primary prostate tumors and 100% of metastatic tumors (Taylor et al., 2010). Androgens induce the accumulation of TORC2 complex, rapamycin insensitive chaperone of mTOR and stress activated protein kinase interacting protein 1 in the nucleus, thus stimulating TORC2 to activate Akt (Fang et al., 2012). Activated AKT can stimulate many downstream functions via its kinase activity, including glycogen synthase kinase 3 (GSK3), tuberous sclerosis complex (TSC), FOXO transcription factors, NF-kappa-B and Bcl-2 family members BAD, which regulate a range of cellular processes (Liu et al., 2009; Courtney et al., 2010). It is estimated that genomic phosphatase and tensin homolog gene (PTEN) alterations, which is a negative inhibitor of PI3K/AKT pathway, occur in 9–45% of high-grade prostate intra-epithelial neoplasia (HG-PIN), 20–60% of localized prostate cancer, and up to 100% of cases of metastatic prostate cancer (Taylor et al., 2010; Jia et al., 2013).

 Src Signaling Pathway

Preclinical studies have confirmed that non receptor tyrosine kinase c-Src and Src family kinase (SFK) regulate a complex signal network, driving the development of castration-resistance prostate cancer and bone metastasis. (Cai et al., 2011). After the establishment of bone metastasis, prostate cancer cells destroy the balance of osteoclasts and osteoblasts by secreting a variety of molecules, such as growth factors and cytokines that disrupt the normal process of bone maintenance and reconstruction (Yang et al., 2001; Mundy, 2002). The balance is in favor of osteoblastogenesis, which explains the usual condensing aspect of PCa-derived bone metastases. Src activity specifically affects ruffled borders of osteoclasts (essential for bone resorption), through dynamic regulating the interactions of actin cytoskeleton and formation of podosomes (Horne et al., 2005; Destaing et al., 2011). Src and other SFKs also play important roles in the antiapoptotic signal transduction of RANKL and other tumor necrosis factor family members in osteoclasts (Xing et al., 2001). One essential role for Src in osteoblasts has also been demonstrated that reduction of Src expression decreases osteoblast(responsible for bone formation) proliferation and increases differentiation (Marilena et al., 2000).

Recently, a large number of studies have shown that the activation of SRC is an important mediator of AR signaling. (Asim et al., 2008). AR can form a tertiary complex with the scaffold protein modulator of non-genomic actions of the estrogen receptor (MNAR/PELP1) and Src (Unni et al., 2004). Initially, Src is inactive within this complex. However, when AR binds to Src, this results in the activation of Src in this complex (AR/MNAR/Src) and the subsequent activation of a downstream effector, MEK (Unni et al., 2004). Subsequent studies have shown that AR-induced Src activation can promote cell proliferation through cell cycle progression from G1 phase to S phase (Migliaccio et al., 2002).

 MAPKs Signaling Pathway

The MAPKs signaling cascade play important roles in regulating diverse biological functions including cell proliferation, motility and survival, which are essential to prostate carcinogenesis (Rossomando et al., 1989; Armenia et al., 2018; Abida et al., 2019). Studies of DHT-responsiveness in prostate cancer cells show that DHT treatment induces phosphorylation of ERK-1/2 within 1–2 min and peak levels of phosphorylation within 5–10 min (Liao et al., 2013). Activated ERK-1/2 then translocate to the nucleus and directly interact with and phosphorylate transcription factors (TFs), such as nuclear ETS domain-containing Elk1 (Marais et al., 1993; Gille et al., 1995; Yang et al., 1998). Elk1 transcriptionally regulates immediate early genes (IEGs) such as c-fos (Gille et al., 1995; Unni et al., 2004), and regulates the expression of several genes related to cell proliferation (Marais et al., 1993; Unni et al., 2004). In addition, recent studies showed that other molecules induce prostate cancer via MAPK signaling. Jason et al. reported that ADP-ribosylation factor 1 (ARF1), a crucial regulator in vesicle-mediated membrane trafficking and involved in the activation of signaling molecules, promotes the occurrence of prostate cancer via targeting oncogenic MAPK signaling (Davis et al., 2016). Gonzalo et al. reported that epidermal growth factor (EGF) could stimulate G0/G1-S transition via p38 MAPK to overcome the growth restriction of androgen deprivation in prostate cancer cells (Rodriguez-Berriguete et al., 2016).

 JAK-STAT3 Signaling Pathway

Janus kinases (JAK) signal transducers and activator of transcription (STAT) pathway play an important role in differentiation, hematopoiesis, immune function and cell growth (Bolli et al., 2003). Recently, accumulating evidence indicated that IL-6 is indispensable for activation of JAK/STAT pathway, which is involved in the oncogenesis of prostate cancer (Liu X. et al., 2012). Compared with men with normal prostates, benign prostatic hyperplasia, prostatitis and localized disease, approximately 50% of patients with advanced prostate cancer have increased levels of serum IL-6 (Twillie et al., 1995). Upon the binding of IL-6 to the IL-6 receptor, JAK-1 and STAT-3 become activated in sequence (C Schindler and Jr, 1995). L Tam et al. reported that cytoplasmic expression of IL-6 receptor and pSTAT3 Tyr705 are associated with the shortened biochemical recurrence time and death time from hormone relapse, respectively. Therefore, it is reasonable to target this pathway in hormone-refractory prostate cancer treatments (Tam et al., 2007).

 Ca<sup>2+</sup> Signaling Pathway

Ca2+signaling is also involved in prostate cancer progression (Figiel et al., 2019; Chalmers and Monteith et al., 2018). Increased calcium intake from dairy products has been considered as a risk factor for prostate cancer (Foradori et al., 2007; Flourakis and Prevarskaya, 2009). As a primary signaling molecule, extracellular Ca2+ works through the Ca2+-sensing receptor (CaR, a G protein coupled receptor) which directly regulates cell signal transduction and the Ca2+ channels (Vaz et al., 2015). Depletion of intracellular Ca2+ stores serves as a signal for the activation of Ca2+ influx across the plasma membrane. The proteins STIM1 and ORAI1 were identified as the key components of store-operated Ca2+ entry (SOCE). When Ca2+ is released from intracellular Ca2+ pool, Ca2+ dissociates from a luminal EF hand motif of STIM1. As a consequence, STIM1 proteins aggregate and recruit Orai1 Ca2+channels, which then mediate SOCE (Kilch et al., 2016).

Recently, Huang et al. found that Ca2+ via CaR-mediated signaling induces filamin A cleavage, which is an actin-binding protein, and promotes the migration of AR-deficient and highly metastatic prostate cancer cells (Huang et al., 2016). In one additional study, Christian demonstrated that transient receptor potential melastatin 4 channel (TRPM4) is activated by a rise in intracellular Ca2+ in prostate cancer cells. Upon activation, a Na+ influx via TRPM4 depolarizes the membrane potential, which reduces the driving force for Ca2+ and limits SOCE, and thus promotes migration of androgen-insensitive prostate cancer cells (Christian et al., 2015).

 Other Genomic Alterations in Castration-Resistant Prostate Cancer

Prostate cancer is characterized by a high genetic heterogeneity due to genomic alterations and instabilities associated with diverse PCa risk factors (Squire et al., 2011; Yap et al., 2016; Ciccarese et al., 2017; Rodrigues et al., 2017), which was evidenced by extensive genomic profiling analysis conducted on primary tumors (Network T. C. G. A., 2015) and on metastatic samples (Dan et al., 2015).

Speckle-type POZ protein (SPOP) is the substrate-binding subunit of a cullin-3 (CUL3)-based E3 ubiquitin ligase complex, which mediates the ubiquitylation and degradation of many target proteins. SPOP binds to the substrates through its N-terminal meprin and traf homology (MATH) domain, whereas it interacts with cullin-3 via BTB domain on its C terminal (Pintard et al., 2003; Xu et al., 2003; Zhuang et al., 2009). Recent cancer whole-genome and exome sequencing studies have shown that SPOP is the most frequently mutated gene (in up to 15% of cases) in primary prostate cancer (Barbieri et al., 2012; Network T. C. G. A., 2015). Interestingly, all SPOP somatic mutations identified in prostate cancer are clustered in its substrate binding MATH domain, thus having a dominant-negative effect on substrate binding and degradation (Theurillat et al., 2014). Recent studies have unanimously reported that SPOP interacts with bromodomain and extraterminal (BET) proteins that largely act as transcriptional coactivators and play vital roles in cell cycle, apoptosis, migration and invasion in physiological conditions. In addition, SPOP also promotes the ubiquitylation and proteasomal degradation of bromodomain-containing protein 2 (BRD2), BRD3 and BRD4, (Dai et al., 2017; Janouskova et al., 2017; Zhang et al., 2017). Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer (French et al., 2003; Crawford et al., 2008; Belkina and Denis, 2012). Recently, Janouskova et al. reported prostate cancer–associated SPOP mutants impaired its binding to BET proteins, leading to the reduced proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens, which subsequently causes resistance to BET inhibitors (Janouskova et al., 2017). Similar study has also demonstrated that SPOP-mutated prostate cancer cell lines and patient-derived organoids were intrinsically resistant to BET inhibitor-induced growth arrest and apoptosis (Dai et al., 2017). Furthermore, Dai et al. provided that stabilization of BRD4 may be a molecular mechanism for resistance to BET inhibitors in patients with prostate cancer bearing SPOP mutations (Dai et al., 2017). Taken together, these findings offer mechanistic insights into how SPOP mutations influence prostate cancer.

The TMPRSS2-ERG fusion gene arising from genetic rearrangement (fusion of encoding transmembrane protease serine 2, TMPRSS2 gene, and EST-related gene, ERG) has also been a central focus in prostate cancer, which leads to aberrant expression of the ETS transcription factor ERG (Tomlins et al., 2005; Kandoth, 2013). TMPRSS2-ERG is the most common gene rearrangement in prostate cancer and is present in approximately 50% of prostate cancer tissues in Western countries (Cary and Cooperberg, 2013). Previous studies indicated that ERG overexpression was driven by hijacking of androgen-responsive elements within the TMPRSS2 promoter (Tomlins et al., 2005; Wang et al., 2007; Thangapazham et al., 2014). However, Kron et al. found that the molecular process is more complex. Their study indicated that the frequent deletion allows a cluster of regulatory elements (CORE) in the TMPRSS2 promoter to expand into the rearranged ERG allele. This expanded CORE contains some CREs within the ERG locus that can promote ERG overexpression. Studies also revealed that overexpressed ERG co-opts prostate-specific master regulatory transcription factors, including AR, HOXB13 and FOXA1, in a process facilitated by their physical interaction with ERG and actives NOTCH signaling in primary prostate cancer (Kron et al., 2017). ERG overexpression is now an instrumental indicator in the diagnosis of prostate cancer. In addition, Graff et al. recently found that obesity and height might be correlated with the development of TMPRSS2-ERG-positive prostate cancer (Graff et al., 2018). Collectively, the functions and mechanisms of TMPRSS2-ERG increase the opportunities for finding new therapeutic targets for prostate cancer(Wang et al., 2017; Kong et al., 2020).

 Natural Compounds That Exert Anti-Prostate Effects

Natural compounds that have been found to inhibit prostate cancer cells proliferation/tumor growth, promote prostate cancer cells apoptosis, or modulate specific signaling pathways involved in prostate cancer in vivo and in vitro are categorized and presented according to their source of isolation (marine organisms, microorganisms and plants) and the structural scaffolds. Besides the effects on prostate cancer cells growth or apoptosis, special emphasis was given to the mechanism of action of a compound interfering specific signaling pathways involved in prostate cancer.

Natural Compounds Obtained From Marine Organisms or Microorganisms

As is well known, marine organisms or microorganisms possess the capacity to produce a large amount of diverse secondary metabolites with unique structural features and biological properties. Thus, marine and microbial organisms represent interesting and important sources of single molecules with promising skeletons and significant anti-prostate cancer activity. Up to now, a total of 24 natural compounds (Figures 3) isolated from marine organisms have been found to exhibit significant anti-prostate cancer activity either in vivo or in vitro. Detailed information about the compounds origin, activity and mechanism of action is listed in Table 1. Most of them exhibit antiproliferative, apoptosis inducing or metastasis inhibitory activities, with various acting mechanisms such as induction of autophagy, inhibition of AR activation, PI-3K/AKT/mTOR or JAK/STAT signaling pathways (Senderowicz et al., 1995; Liu et al., 2006; Wang WL. et al., 2008; Hellsten et al., 2008; Gantar et al., 2012; Meimetis et al., 2012; Shin et al., 2013; Liberio et al., 2015; Liu et al., 2016). Especially, frondoside A not only caused cell type specific cell cycle arrest and induction of caspase-dependent or -independent apoptosis in vivo but also significantly inhibited the cell growth of PC-3 and DU145 with a notable reduction of lung metastasis and decrease of circulating tumor cells in the peripheral blood (Dyshlovoy et al., 2016). In addition, gliotoxin, chaetocin and chetomin exhibited antiangiogenic effects in vitro and attenuated tumor growth mainly by disrupting the HIF-1α/p300 complex, which makes them attractive molecules for the design of future chemotherapeutic agents (Cook et al., 2009).

Natural compounds obtained from marine organisms or microorganisms with anti-prostate cancer activities.

Natural compound Sort Name of microorganisms Cell type Observation Activity Mechanism of action Refs
C-phycocyanin Proteins Limnothirix sp. LNCaP In vitro Induction of apoptosis Increase of radical oxygen species (ROS) generation; increase of caspase-9 and caspase-3 activities. Gantar et al. (2012)
Eusynstyelamide B(1) Alkaloids Didemnum candidum LNCaP In vitro Antiproliferation Induction of G2 cell cycle arrest; increase of CHK2 phosphorylation; upregulation of p21CIP1/WAF1; decrease of CDC2 expression. Liberio et al. (2015)
Frondoside A(2) Triterpene glycosides Cucumaria okhotensis DU145 LNCaP PC3 22Rv1 VCaP In vivo Antiproliferation Induction of G2/M cell cycle arrest; upregulation of Bax, Bad, PTEN, cleavage of PARP and caspase-3; downregulation of anti-apoptotic proteins (survivin and Bcl-2); inhibition of pro-survival autophagy by upregulation of phospho-mTOR. Dyshlovoy et al. (2016)
Induction of apoptosis
In vitro Inhibition of metastasis
Inhibition of tumor growth
Galiellalactone(3) Ketones Galiella ruffle DU145 LNCaP PC3 In vivo Induction of apoptosis Inhibition of Stat3 activity; downregulation of the expressions of Bcl-2, Bcl- xL, c-myc and cyclin D1. Hellsten et al. (2008)
In vitro Inhibition of tumor growth
Chaetocin(4) Ketones Trichoderma virens PC3 In vivo Antiangiogenesis Disruption of the HIF-1α/p300 complex. Cook et al. (2009)
In vitro Inhibition of tumor growth
Chetomin(5) Ketones Trichoderma virens PC3 In vivo Antiangiogenesis Inhibition of tumor growth Disruption of the HIF-1α/p300 complex. Cook et al. (2009)
In vitro
Gliotoxin(6) Ketones Trichoderma virens PC3 In vivo Antiangiogenesis Disruption of the HIF-1α/p300 complex. Cook et al. (2009)
In vitro Inhibition of tumor growth
Halichondramide(7) Trisoxazol-e macrolides Chondrosia corticata PC3 In vivo Antiproliferation Inhibition of metastasis The suppression of PRL-3 via downregulation phosphoinositide 3-kinase (PI3K) subunits p85 and p110 the expression; downregulation of matrix metalloproteases (MMPs). Shin et al. (2013)
Lejimalide B(8) Macrolide-s Eudistoma cf. rigida LNCaP In vivo Antiproliferate Induction of apoptosis Induction of G0/G1 cell cycle arrest and expression of p21waf1/cip1; downregulation of the expression of cyclin A, E, D survivin, p21B and BNIP3. Wang et al. (2008b)
PC3
Jasplakinolide(9) Cyclopent-apeptides Jaspis johnstoni LNCaP PC3 In vitro Antiproliferation Not investigated. Senderowicz et al. (1995)
TSUPrl
Malformin A1(10) Cyclopent-apeptides Aspergillus niger LNCaP PC3 In vitro Antiproliferation Induction of apoptosis and necrosis Induction of mitochondrial damage and autophagy. Liu et al. (2016)
Stellettin A(11) Triterpene-s Geodia japonica LNCaP In vivo Induction of oxidative stress and apoptosis Upregulation of FasL and caspase-3 expression. Liu et al. (2006)
Niphatenone B(12) Glycerol ethers Niphates digitalis LNCaP PC3 In vitro Antiproliferation Binding with the activation function-1 (AF1) region of the AR N-terminus domain (NTD). Meimetis et al. (2012)
4H-1,3-dioxin-4-one-2,3,6-trimethyl Dioxin Trichoderma atroviride PC3 In vitro Induction of apoptosis Increase of expression of caspase -3 Ks et al. (2019)
In vivo
Alternol unknown mutant fungus PC-3; 22RV1;BPH1 in vitro Antiproliferation;Induction of apoptosis; Interaction with multiple Krebs cycle enzymes Li et al. (2019)
Hapalindole H (13) indole-alkaloid Fischerella muscicola PC-3 in vitro Antiproliferation; Through the intrinsic mitochondrial pathway Acua et al. (2018)
Heteronemin (14) sesterterpenoid Hyrtios sp. LNcap; PC3 In vitro Induction of apoptosis Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90 Lee et al. (2018)
In vivo
xanthoquinodin JBIR-99 (15) Quinolines Parengyodontium album MEXU 30054 PC-3 in vitro Induction of apoptosis Though intrinsic and extrinsic apoptotic pathways Anaya-Eugenio et al. (2019b)
Giluterrin (16) alkaloid Aspergillus terreus P63 PC-3 in vitro Antiproliferation Not investigated Gubiani et al. (2019)
Elaiophylin (17) antibiotic Actinomycete streptomyces 22Rv1； VCaP in vitro blocking RORg transcriptional regulation activities Inhibition of the expression of RORg target genes AR and AR variant Zheng et al. (2020)
in vivo
Urupocidin C (18) bicyclic guanidine alkaloid Monanchora pulchra 22Rv1; in vitro Induction of apoptosis Though mitochondria targeting Dyshlovoy et al. (2020)
LNCaP
Pseudopterosin H diterpene glycosides Pseudopterogorgia elisabethae PC-3 in vitro reducing PC-3 cell viability Inducing apoptosis and downregulating the production of intracellular reactive oxygen species Bowers et al. (2021)
Nalidixic acid (19) quinolone antibiotic Streptomyces sp. (C-7) PC3 in vitro cytotoxic effect Not investigated Arora et al. (2018)
Discorhabdin L (20) alkaloid Latrunculia sp. in vivo Inhibition of cell growth Not investigated Harris et al. (2018)

Natural compounds obtained from marine organisms or microorganisms with anti-prostate cancer activities.

 Natural Compounds Isolated From Plants

Medicinal plants have always been a very good source of drugs, which could produce plenty of secondary metabolites with high structural diversity and versatile bioactivities. Many candidates with promising anti-prostate activity have been reported, including 7 alkaloids, 23 flavanoids, 25 terpenoids, 13 polyphenols, 10 lignans and 48 other compounds (Figures 4–9). Almost all these candidates show anti-prostate cancer activities via anti-proliferation, apoptosis induction or metastasis and invasion inhibition, involved in canonical AR signaling and non-AR signaling like caspase cascades, AKT/mTOR pathway, MAPKs pathway, NF-κB pathway, Ca2+ pathway and JAK/STATs pathway. Additionally, there exist other acting mechanisms, for example, anibamine exhibited anti-prostate cancer activity by binding to the chemokine receptor CCR5; fisetin inhibited tumor growth by downregulating the expression of NudC protein, MMP-2 and MMP-9; lycopene showed anti-prostate cancer effects by inhibiting androgen receptor element and signaling of insulin-like growth factor-1 (Afaq et al., 2008; Khan et al., 2008; Bureyko et al., 2009; Wertz, 2009; Zhang et al., 2010b; Chien et al., 2010; Suh et al., 2010; Tang et al., 2011; Holzapfel et al., 2013; Mukhtar et al., 2015). Detailed information is provided in Tables 2–7.

Alkaloids obtained from plants with anti-prostate cancer activities.

Flavanoids obtained from plants with anti-prostate cancer activities.

Terpenoids obtained from plants with anti-prostate cancer activities.

Polyphenols obtained from plants with anti-prostate cancer activities.

Lignans obtained from plants with anti-prostate cancer activities.

Other compounds obtained from plants with anti-prostate cancer activities.

Alkaloids obtained from plants with anti-prostate cancer activities.

Natural compound Botanical name Cell type Observation Activity Mechanism of action Refs
Anibamine(21) Aniba panurensis DU145 M12 In vitro Antiproliferation Binding to the chemokine receptor CCR5. Zhang et al. (2010b)
PC3 Inhibition of metastasis and invasion
Berberine(22) Coptis chinensis Franch. DU145 LNCaP PC3 In vitro Antiproliferation Induction of apoptosis and programmed necrosis Inhibition of p53-Cyp-D association via decreasing the ROS production; downregulation of HIF-1α and VEGF expression; induction of G1 and G2/M cell cycle arrest by activating ATM-Chk1; induction of caspase-3 and -9 activation; upregulation of bax/bcl-2 expression. Wang et al. (2012), Zhang et al. (2014)
PC82 PWR1E In vivo
Pipernonaline(23) Piper longum L. DU145 LNCap PC3 In vitro Induction of apoptosis Induction of sub-G1 and G0/G1 cell cycle arrest through downregulation of CDK2, CDK4, cyclin D1 and cyclin E; upregulation of procaspase-3/PARP cleavage; induction of ROS production and intracellular Ca2+, and mitochondrial membrane depolarization. Lee et al. (2013b)
Piperlongumine(24) Piper longum L. LNCaP In vitro Antiproliferation Induction of G2/M phase cell cycle arrest; upregulation of bax/bcl-2 expression; activation of caspase-3; downregulation of PARP expression. Kong et al. (2008)
PC3
Sanguinarine(25) Argemone mexicana L. PC3E RWPE1 TEM4-18 In vitro Cytotoxicity Inhibition of RGS17 activity. Bodle et al. (2017)
Piperine (26) Piper nigrum L. and Piper longum L. DU145 in vitro Inhibition of migration progression downregulating the Akt/mTOR/MMP-9 signaling pathway Yuan and Ying (2018)
Neferine (27) Nelumbo nucifera Gaertn. PC3, CD44+ in vitro Inhibition of proliferation and migration through p38 MAPK/JNK activation Erdogan and Turkekul (2020)
CSCs； LNCaP

Flavanoids obtained from plants with anti-prostate cancer activities.

Natural compound Botanical name Cell type Observation Activity Mechanism of action Refs
Apigenin(28) Distributed in various plants C4-2B DU145 In vitro Antiproliferation Binding with IKKα; inhibition of NF-ĸB/p65 activity; inhibition of apoptosis proteins and Ku70-Bax interaction; inhibition of tumor suppressor ER-β degradation; inhibition of class I HDACs expression; inhibition of ABCB1 expression and sensitivity improvement of docetaxel-resistant prostate cancer cells to docetaxel treatment. Zhu et al. (2013), Salmani et al. (2017)
PC3 In vivo Anti-invasion
22Rv1 Suppression of prostate cancer growth
Baicalein(29) Scutellaria baicalensis Georgi LNCaP PC3 In vitro Antiproliferation Induction of G1 cell cycle arrest; inhibition of androgen receptor (AR) expression. Haimson et al. (2005)
In vivo Inhibition of tumor growth
Cajanol(30) Cajanus cajan (L.) Huth PC3 In vitro Induction of apoptosis Induction of G1 and G2/M cell cycle arrest; modulation of the ERa-dependent PI3K pathway and induction of GSK3 and CyclinD1 activation. Haimson et al. (2005)
Cryptocaryone(31) Cryptocarya wightiana Thwaites PC3 In vitro Antiproliferation Induction of caspase-8 and 3 activation; upregulation of DR5 surface expression; induction of Fas clustering and the association of downstream signaling molecules, including FADD and procaspase-8; induction of DR4 and DR5 aggregation. Chen et al. (2010)
Induction of apoptosis
CG901(32) Artocarpus altilis (Parkinson) Fosberg C4-2B DU145 In vitro Antiproliferation Selective inhibition of prostate cancer cell lines proliferation and mouse xenograft growth by inhibiting the expression of STAT3 target genes. Jeon et al. (2015a)
PC3 In vivo
Daidzein(33) Glycine max (L.) Merr. DU145 In vitro Antiproliferation Decrease the expression of VEGF and AR genes; induction of G2/M phase in the PC3 cells by downregulating Cyclin B1 and CDK1, and upregulating CDK inhibitors (p21 and p27); upregulation of Fas ligand (FasL) and the expression of proapoptotic Bim; downregulation of the expression of p-FOXO3a and increase of the nuclear stability of FOXO3a. Labow and Layne, (1972)
LNCaP PC3 In vivo Induction of apoptosis
Fisetin(34) Distributed in various plants DU145 LNCaP PC3 In vitro Antiproliferation Downregulation of the expression of NudC protein; downregulation of MMP-2 and MMP-9 expressions. (Shimoi, 1998; Afaq et al., 2008; Khan et al., 2008; Chien et al., 2010; Suh et al., 2010; Mukhtar et al., 2015)
22Rv1 In vivo Inhibition of tumor growth
Formononetin(35) Trifolium pratense L. PC3 In vitro Antiproliferation Induction of G0/G1 phase cell cycle arrest; inhibition of the IGF-1/IGF-1R pathway and alteration of the Bax/Bcl-2 ratio; downregulation of expression levels of cyclin D1 and CDK4. (Huang et al., 2013; Bi, 2014; Li et al., 2014)
RWPE1 In vivo Induction of apoptosis
Flavokawain B(36) Piper methysticum G.Forst. DU145 In vitro Antiproliferation Selective inhibition on androgen receptor (AR)-negative prostate cancer cell growth; induction of apoptosis with associated increased expressions of proapoptotic proteins: death receptor-5, Bim, Puma and downregulation of XIAP and survivin expressions. Tang et al. (2010)
PC3 In vivo Induction of apoptosis
LNCaP
LAPC4
Genistein(37) Glycine max (L.) Merr. DU145 PC3 PC-3M In vitro Inhibition of migration Prevention of metastasis by directly binding to MEK4 and downregulation of p38 expression; downregulation of expression and activity of MMP-2. (Li and Sarkar, 2002; Hsu et al., 2010)
In vivo
Ginkgetin(38) Ginkgo biloba L. DU145 In vitro Antiproliferation Induction of apoptosis Inhibition of tumor growth Induction of G0/G1 cell cycle arrest; selective suppression of STAT3 Tyr705 phosphorylation but not through inhibiting upstream tyrosine kinases and tyrosine phosphatase. Jeon et al. (2015b)
LNCaP PC3 In vivo
Isoliquiritigenin(39) Distributed in various plants D4-2B In vitro Antiproliferation Downregulation of the expression of NudC protein; downregulation of MMP-2 and MMP-9 expressions. Zhang et al. (2010a)
LNCaP In vivo Inhibition of tumor growth
Isoangustone A(40) Ginkgo biloba L. DU145 PC3 In vitro Antiproliferation Induction of p27kip1 tumor suppressor gene accumulation by attenuating p27kip1 at Thr 187 phosphorylation; inhibition of CDK2 activation through binding with the CDK2 complex; inhibition of mTOR kinase activity by binding with the mTOR complex. Lee et al. (2013a)
In vivo Induction of apoptosis
Inhibition of tumor growth
Luteolin(41) Distributed in various plants LNCaP PC3 In vitro Antiproliferation Inhibition of ANO1 expression; inhibition of the expression and/or function of ARs via regulation of prostate derived Ets transcription factor(PDEF); inhibition of IGF-1/IGF-1R system; decrease of the expression of E-cadherin through MDM. Seo et al. (2017)
In vivo Prevention of metastasis
Licochalcone A(42) Glycyrrhiza glabra L. LNCaP In vitro Antiproliferation Induction of G2/M cell cycle arrest; downregulation of cyclin B1 and cdc2 expression; inhibition of phosphorylation of retinoblastoma (Rb); decrease of expression of transcription factor E2F, cyclin D1, CDKs 4 and 6; increase of expression of cyclin E. Su et al. (2017)
Induction of apoptosis
Quercetin-6-C-b-D-glucopyranoside(43) Ulmus wallichiana Planch. DU145 In vitro Antiproliferation Induction of apoptosis via induction of cleaved PARP and Cas-3; induction of G0/G1 cell cycle arrest; inhibition of reactive oxygen generation and AKT/mTOR survival pathway via directly binding with aryl hydrocarbon receptor. Hamidullah et al. (2015)
LNCaP PC3 Induction of apoptosis
RWPE1
Quercetin(44) Distributed in various plants DU145 In vitro Induction of apoptosis Increase of expression of c-Jun and its phosphorylation; decrease of expression of HSP72; intervention of BaP toxicity. Asea et al. (2001), Yuan et al. (2004), Chaudhary et al., (2007), Aalinkeel et al. (2008)
LNCaP PC3 In vivo
Xanthohumol(45) Humulus lupulus L. BPH-1 PC3 In vitro Antiproliferation Induction of S and Sub G1 cell cycle arrest; inhibition of NFkB activity and expression. Upregulation of pro- apoptotic proteins Bax and p53 expression. Colgate et al. (2007)
Induction of apoptosis
Vitexicarpin(46) Vitex rotundifolia L.f. PC3 In vitro Induction of apoptosis Induction of G2/M cell cycle arrest. Meng et al. (2012)
2′,4′-dihydroxychalcone (47) Herba oxytropis PC3 In vitro Induction of apoptosis Induction of G1/S cell cycle arrest. Sheng et al. (2015)
Auriculasin (48) Flemingia macrophylla var. philippinensis (Merr. & Rolfe) H.Ohashi LNCaP-FGC；RWPE-1 In vitro Induction of apoptosis; antiproliferation Regulation of the PI3K/AKT/mTOR pathway in LNCaP prostate cancer cells;ROS accumulation Cho et al. (2018)
In vivo
Naringenin (49) citrus fruits and tomatoes MAT-LyLu cells In vitro Inhibition of metastasis Blocking voltage-gated sodium channels Gumushan Aktas and Akgun (2018)
Casticin (50) Vitex rotundifolia L.f., DU 145 In vitro Inhibition of prostate cancer cell metastasis Inhibition of the protein levels of AKT, GSK3αβ, Snail, and MMPs (MMP-2, -9, -13, and -7);diminision of the expressions of NF-κB p65, GRB2, SOS-1, MEK,p-ERK1/2, and p-JNK1/2 Lin et al. (2019)

Terpenoids obtained from plants with anti-prostate cancer activities.

Natural compound Botanical name Cell type Observation Activity Mechanism of action Refs
Artemisinin(51) Artemisia annua L. DU145 In vitro Induction of apoptosis Increase of synthesis, and cleavage of procaspase-9, cleavage of caspase-3, and PARP-1 degradation. Nakase et al. (2009)
PC3
Betulinic Acid(52) Bacopa monnieri (L.) Wettst. LNCaP In vitro Induction of apoptosis Activation of selective proteasome-dependent degradation of the transcription factors specificity protein 1(Sp1), Sp3, and Sp4; regulation of survivin and VEGF expression; downregulation of NF-kappaB expression. Chintharlapalli et al. (2007)
In vivo Inhibition of tumor growth
Celastrol(53) Tripterygium wilfordii Hook.f. LNCaP PC3 In vitro Induction of apoptosis Accumulation of ubiquitinated proteins and three natural proteasome substrates IKB-A, Bax, and p27. Wolfram et al. (2014)
In vivo
Caseamembrin C(54) Casearia membranacea PC3 In vitro Antiproliferation Downregulation of Bcl-2 and Bcl-xL expression; upregulation of Mcl-1S protein and activation of caspase-9 and caspase-3. Huang et al. (2004)
Induction of apoptosis
Glycyrrhizin(55) Glycyrrhiza glabra L. DU145 LNCaP In vitro Antiproliferation Downregulation of the expression of caspase-3 and caspase-8. Thirugnanam et al. (2008)
Induction of apoptosis
Lycopene(56) Distributed in various plants PC3 In vitro Antiproliferation Antimetasis Inhibition of the androgen receptor element, resulting in decreased PSA velocity; inhibition signaling of insulin-like growth factor-I (IGF-I); decrease of the expression of αvβ3 and αvβ5 integrin. (Bureyko et al., 2009; Wertz, 2009; Tang et al., 2011; Holzapfel et al., 2013)
In vivo Induction of apoptosis
Oridonin(57) Isodon rubescens (Hemsl.) H.Hara PC3 In vivo Induction of apoptosis Increase of expression of P21 and the mRNA level of beclin; increase of caspase-3 activity. (Deepak and Handa, 2000; Xiang et al., 2012; Ming et al., 2016)
In vitro Inhibition of tumor growth
Antiproliferation
Pachymic acid(58) Poria cocos DU145 LNCaP In vitro Antiproliferation Decrease of prostaglandin synthesis and AKT activity. Gapter et al. (2005)
Induction of apoptosis
Pseudolaric acid B(59) Larix kaempferi (Lamb.) Carrière DU145 In vitro Antiproliferation Increase of ROS generation and Bcl-2 degradation. Zhao et al. (2012)
Induction of apoptosis
Sugiol(60) Salvia prionitis Hance DU145 In vitro Antiproliferation Induction of G0/G1 cell cycle arrest; downregulation the expression of STAT3; interaction with TKT. Jung et al. (2015)
LNCaP
PC3
Triptolide(61) Tripterygium wilfordii Hook.f. DU145 In vitro Antiproliferation Decrease of CDK7-mediated phosphorylation; disruption of the phosphorylation of AR through XPB/CDK7. Fei et al. (2016)
LNCaP PC3 In vivo Induction of apoptosis
22Rv1
Ursolic Acid(62) Distributed in various plants DU145 LNCaP In vitro Antiproliferation Upregulation of DR5 activation of JNK; inhibition of NF-κB and STAT3 pathways. (Deepak and Handa, 2000; Shanmugam et al., 2011; Meng et al., 2015)
In vivo Induction of apoptosis
Zerumbone(63) Zingiber zerumbet (L.) Roscoe ex Sm. DU145 In vitro Antiproliferation Increase of MPM-2 expression; increase of Bcl-2 and Bcl-xL phosphorylation; induction of Cdk1 activity; induction of Cdc25C downregulation. Chan et al. (2015)
Induction of apoptosis
HRPC
PC3
β-elemene(64) Distributed in various of plants DU145 PC3 In vitro Antiproliferation Downregulation of Bcl-2 expression; increase of cytochrome c; activation of PARP and caspase-3, -7, -9, and -10. Li et al. (2010)
Induction of apoptosis
7-xylosyl-10-deacetyl paclitaxel(65) Taxus wallichiana Zucc. PC3 In vitro Antiproliferation Induction of G2/M cycle arrest; upregulation of pro-apoptotic Bax and Bad protein expressions and downregulation of anti- apoptotic Bcl-2 and Bcl-XL expressions. Jiang et al. (2008)
Induction of apoptosis
25-OCH3-PPD (GS25)(66) Panax notoginseng (Burkill) F.H.Chen DU145 In vitro Induction of apoptosis Decrease of MDM2 protein level; increase of the protein levels of the wild-type p53, Bax, cleaved-PARP. Wang et al. (2008a)
LNCAP In vivo
PC3
Bakuchiol (67) Cullen corylifolium (L.) Medik. PC3 In vitro Inhibition of cell proliferation and migration; Inactivating NF-κB signaling via AR and ERβ Miao et al. (2017)
Afrocyclamin A (68) Androsace umbellata (Lour.) Merr. DU145 In vitro; Induction of apoptosis;inhibition of migration and invasion; inhibition of cell growth Via the PI3k/Akt/mTOR pathway Sachan et al. (2018)
In vivo
Corosolic acid (69) Eriobotrya japonica (Thunb.) Lindl.; Crataegus pinnatifida Bunge; Actinidia chinensis Planch. PC-3;DU145;22RV1;WPMY-1 In vitro Inhibition of cell growth;Induction of apoptosis The activation of endoplasmic reticulum (ER) stress-associated two pro-apoptoticsignaling pathways Ma et al. (2018)
3-oxo-4-oxa-A-homo-25,26,27-trinordammarano-24,20-lactone triterpene (70) Cleome khorassanica Bunge & Bien DU-145 ； LNCaP In vitro Cell growth inhibition Not investigated Sajjadi et al. (2018)
20,25-dihydroxy-3-oxodammarane triterpene (71) Cleome khorassanica Bunge & Bien DU-145 ； LNCaP In vitro Cell growth inhibition Not investigated Sajjadi et al. (2018)
Britanin (72) Inula linariifolia Turcz. PC-3； PC-3-LU； DU-145 In vitro; Inhibition of cell proliferation, migration, and motility Through PI3K/Akt/NF-κB Signaling Pathways Zeng et al. (2020)
In vivo
Linalool (73) herbs, spices and fruits 22Rv1 In vitro; Antiproliferation;Induction of apoptosis;Inhibition of migration invasion Mitochondria-mediated intrinsic and death-receptor-mediated extrinsic pathways; inhibition of expression of Ki-67 and PCNA in the 22Rv1 xenograft model. Zhao et al. (2020)
In vivo
β-elemonic acid (74) Boswellia carterii Birdw DU145, PC-3 and 22RV1 In vitro Induction of apoptosis Through the suppression of JAK2/STAT3/MCL-1 and NF-ĸB signal pathways Bao et al. (2021)
Heliantriol B2 (75) Chuquiraga erinacea subsp. erinacea (Asteraceae) PC-3; In vitro Antiproliferation;Induction of apoptosis;Inhibition of migration invasion Not investigated Castro et al. (2019)
LNCaP

Polyphenols obtained from plants with anti-prostate cancer activities.

Natural compound Botanical name Cell type Observation Activity Mechanism of action Refs
Atraric acid (76) Prunus africana (Hook.f.) Kalkman LNCaP In vitro Inhibition of prostate cancer cell growth Inhibition of AR nuclear translocation. Schleich et al. (2006)
Curcumin(77) Curcuma longa L. DU145 In vitro Antiproliferation Inhibition of the expression of MT1-MMP and MMP2 proteins; inhibition of the DNA-binding ability of NICD. Yang et al. (2017)
PC3
Ellagic Acid(78) Distributed in various plants LNCaP In vitro Antiproliferation Induction of apoptosis Increase of Bax/Bcl2 ratio and increase caspases 3, caspases 6, caspases 8, and caspases 9 and PARP cleavage; inhibition of mTOR activation and reduction of intracellular levels of β-catenin; downregulation of the expressions of anti-apoptotic proteins, silent information regulator 1 (SIRT1), human antigen R (HuR) and heme oxygenase-1 (HO-1). Vanella et al. (2013)
Gallic Acid(79) Toona sinensis (Juss.) M.Roem. DU145 PC3 22Rv1 In vitro Inhibition of migration Induction of apoptosis Activation of Chk1 and Chk2 and inhibition of Cdc25C and Cdc2 activities; blocking of the p38, JNK, PKC and PI3K/AKT signaling pathways and downregulation of NF-κB protein level; inhibition of MMP2 and MMP 9 gene expression. (Hastak et al., 2003; Kaur et al., 2009)
In vivo
Gossypol(80) Gossypium hirsutum L. DU145 PC3 In vitro Antiproliferation Induction of apoptosis Downregulation of Bcl-2 and Bcl-xl and the upregulation of Bax; activation of caspase3, caspase8 and caspase9 through the ROS-independent mitochondrial dysfunction pathway and the increase of PARP cleavage; suppression of the expression of AP-1and NF-κB blocked the activation of VEGF receptor 2 kinase. Huang et al. (2006)
In vivo
Honokiol(81) Magnolia officinalis PC3 LNCaP In vitro Induction of apoptosis Activation of Bax and/or Bak; decrease of expression of c-Myc. Shigemura et al. (2007)
Myc-CaP In vivo Inhibition of prostate tumor growth
Nordihydroguaiaretic acid(82) Larrea tridentata (DC.) Coville PC3 In vitro Inhibition of migration Antiproliferation Suppression of NRP1 function. Li et al. (2016)
In vivo
Obovatol(83) Magnolia obovata Thunb. PC3 LNCaP In vitro Induction of apoptosis Inhibition of TNF-α and TPA-induced DNA binding activity of NF-κB; translocation inhibition of p65 and p50 into nucleus via decreasing IκB phosphorylation; increase of the apoptotic genes expression: Bax, caspase-3, caspase-9; inhibition of the anti-apoptotic genes expression: Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP). Soyong et al. (2009)
Resveratrol(84) Reynoutria japonica Houtt. DU145 In vitro Induction of apoptosis Downregulation of Bcl-2 and Bcl-xL and upregulation of Bax; activation of caspases-3, -8 and -9 and increased PARP cleavage. Chang et al. (2013)
In vivo
Procyanidin Arachis hypogaea L. DU145 In vitro Antiproliferation Induction of apoptotic cell death and cell cycle arrest at S phase;increase of intracellular ROS level and the decrease of Bcl-2/Bax ratio, and the activation of p53 and caspases-3 Chen et al. (2018)
Sinapic acid (85) various vegetables and fruit species PC3; In vitro Antiproliferation;Induction of apoptosis;Inhibition of migration invasion Increase of the expression of BAX, CASP3, CASP8, CYCS, FAS, TIMP-1 and CDH1,decrease of expression of MMP-9 in PC-3 cells;decrease of in the expressions of CDH2, MMP-2 and MMP-9 in LNCaP cells;increase of caspase-3 activity Eroğlu et al. (2018)
LNCaP
Carvacrol (86) Origanum and Thymus Human OSCC Tca-8113; SCC-25 In vitro Antiproliferation, inhibition of metastasis and invasion;Induction of apoptosis Regulating the cell cycle-associated proteins (P21, CCND1 and CDK4) and apoptosis-associated proteins (Cox2, Bcl-2, and Bax); inhibiting P-FAK, and reducing β-catenin, ZEB1, and MMP-2/9 expression Dai et al. (2016)
Hispolon (87) Phellinus linteus DU145 In vitro Induction of apoptosis Via modulation of mitochondrial and STAT3 pathways Masood et al. (2019)

Lignans obtained from plants with anti-prostate cancer activities.

Natural compound Botanical name Cell type Observation Activity Mechanism of action Refs
Deoxypodophyllotoxin(88) Anthriscus sylvestris (L.) Hoffm. LNCaP PC3 In vitro Antiproliferation Accumulation of the reactive oxygen species, intracellular Ca2+; increase of mitochondrial membrane potential. Kim et al. (2013)
Induction of apoptosis
Magnolol (89) Magnolia officinalis Rehder & E.H.Wilson PC3 in vivo Cytotoxicity Decrease of MMP-2 and MMP-9 expression; decrease of the level of phosphorylated AKT. Lee et al. (2009)
PrEC
Silibinin(90) Silybum marianum (L.) Gaertn. LNCaP 22Rv1 In vitro Antiproliferation Activation of acetyl-CoA carboxylase; reduction in hypoxia-induced NADPH oxidase (NOX) activity; increase of the lipid accumulation and NOX activity; downregulation of HIF-1α expression, lipid levels, clonogenicity and NOX activity. Ting et al. (2016)
In vivo
VB1(91) Vitex negundo L. PC3 In vitro Induction of apoptosis Activation of PARP cleavage. Zhou et al. (2009)
In vivo
Magnoline (92) Phellodendri amurensis cortex 22RV1 In vitro Antiproliferation Disturbance of nutrition metabolism and energy metabolism Sun et al. (2018)
Arctigenin (93) Arctium lappa L. PC-3M In vitro Induction of apoptosis and autophagy Via PI3K/Akt/mTOR inhibition Sun et al. (2021)
2-(5′-allyl-4‴,9‴-dihydroxyphenyl-furan)-3-hydroxy-7-methoxy-8-(6″,7″-dimethyl-furan-2″-one)-chromen-4-one. (94) Hosta plantaginea (Lam.) Aschers LNCaP In vitro Inhibition of cell growth Not investigated Wei et al. (2020)
2-(5′-allyl-3‴,5‴,9‴-trihydroxy-4‴-methoxyphenyl-furan)-3-hydroxy-7,8-furan-ring-chromen-4-one. (95) Hosta plantaginea (Lam.) Aschers LNCaP In vitro Inhibition of cell growth Not investigated Wei et al. (2020)
2,3-dehydrosilychristin (96) Hosta plantaginea (Lam.) Aschers LNCaP In vitro Inhibition of cell growth Not investigated Wei et al. (2020)
silychristin A (97) Hosta plantaginea (Lam.) Aschers LNCaP In vitro Inhibition of cell growth Not investigated Wei et al. (2020)

Other compounds obtained from plants with anti-prostate cancer activities.

Natural compound Sort Botanical name Cell type Observation Activity Mechanism of action Refs
Aloe-emodin(98) Anthraquin-ones Rheum palmatum L. PC3 In vitro Antiproliferation Binding with mTOR complex2；Inhibition of mTORC2 kinase activity and downstream substrates of mTORC2, AKT and PKCa activity. Liu et al. (2012a)
In vivo Suppression of prostate cancer growth
Calcitriol(99) Secosteroids Distributed in various plants C4-2B In vitro Antiproliferation Upregulation of Vitamin D receptor (VDR) expression; induction of BAX expression; increase of cleaved caspase-3 and downregulation of cdk2 expression. Ben-Eltriki et al. (2016)
LNCaP Induction of apoptosis
Diindolylmethane(100) Indoles Distributed in various plants LNCaP PC3 In vitro Antiproliferation Induction of apoptosis Induction a [Ca2+] rise by evoking phospholipase C-dependent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via phospholipase A2-sensitive store-operated Ca2+ channels; regulation of FOXO3a/β-catenin/GSK-3β signaling; regulation of estrogen metabolism and acting as an antiandrogen, finally leading downregulation of the AR and PSA. Wang et al. (2016a)
Diallyl Trisulfide(101) Trisulfides Allium sativum L. DU145 In vitro Induction of apoptosis Downregulation of XIAP protein expression. Kim et al. (2011)
LNCap PC3 In vivo
Embelin(102) Quinones Embelia ribes Burm.f. C4-2B In vitro Antiproliferation Induction of apoptosis Induction of G1 cell cycle arrest; induction of apoptosis by triggering caspase 3 activation and PARP cleavage; inhibition of survivin expression by inhibiting AKT/NF-κB pathway. Xu et al. (2017)
DU145
PC3
ESK246(103) Glycosides Pittosporum venulosum LNCaP In vitro Antiproliferation Inhibition of leucine uptake, leading to reduced mTORC1 signaling, cell cycle protein expression and cell proliferation. Wang et al. (2014)
Ginsenoside Rg3(104) Steroids Panax ginseng C.A.Mey. PC-3M In vitro Antiproliferation Suppression of aquaporin 1 (AQP1) water channel protein expression by activating p38 MAPK. Pan et al. (2012)
Antimetastasis
Guggulsterone(105) Steroids Commiphora mukul (Hook. ex Stocks) Engl. DU145 LNCaP PC3 In vitro Antiproliferation Induction of apoptosis Increase of Bax expression, downregulation of Bcl-xl and Bcl-2 expression; increase of caspase-9 and caspase-8 cleavage; increase of ROI generation by activating JNK; selective inhibition of androgen receptor promoter activity in LNCaP cell. Singh et al. (2005)
PrEC
Guttiferone F(106) Prenylated benzophenones Allanblackia stuhlmannii (Engl.) Engl. LNCaP PC3 In vitro Induction of apoptosis Increase of sub-G1 fraction and DNA fragmentation; down-regulation of androgen receptor expression and phosphorylation of ERK1/2. Li et al. (2015c)
In vivo
Indole-3-carbinol (I3C)(107) Indoles Distributed in various plants LNCaP In vitro Antiproliferation Induction of G1 cell-cycle arrest and downregulation of AR expression and inhibition of AR promoter activity. Hsu et al. (2005)
Juglone(108) Quinones Juglans mandshurica Maxim. LNCaP In vitro Antiproliferation Induction of apoptosis Downregulation of AR expression; increase of caspase-3 and -9 activity. Jiang et al. (2013)
Marchantin M(109) Diphenyls Asterella angusta DU145 LNCaP PC3 In vitro Induction of apoptosis Inhibition of the 20S proteasome activity; induction of microtubule-associated protein-1 light chain-3 beta (LC3B) expression and conversion; induction of RNA-dependent protein kinase-like ER kinase activity; suppression of the PI3K/AKT/mammalian target of rapamycin axis through preventing the activation and expression of AKT. Jiang et al. (2013)
Moniliformediquinone (110) Phenanthradiquinones Dendrobium moniliforme (L.) Sw. DU145 PC3 In vitro Antiproliferation Induction of apoptosis Inhibition of tumor growth Induction of S cell cycle arrest; induction of DNA damage response associated with Chk1, Chk2, c-Jun and JNK activation; induction of caspase-2,-3,7,8 and -9 cleavage through mitochondrial membrane loss and cytochrome c release. Hsu et al. (2014)
In vivo
Oleuropein (111) Glycosides Olea europaea L. LNCaP DU145 BPH-1 In vitro Anti-oxidation Cytotoxicity Not investigated. Acquaviva et al. (2012)
In vivo Inhibition of tumor cell growth and invasiveness
Physapubescin B (112) Steroids Physalis pubescens L. PC3 In vitro In vivo Antiproliferation Downregulation of Cdc25C protein expression; induction of G2/M cell cycle arrest; decrease of Cdc25C level and increase of levels of CyclinB1, P21 and p-Cdk1 (Tyr15). Ding et al. (2015)
Pristimerin (113) Esters Distributed in various plants PC3 In vitro Induction of apoptosis Inhibition of proteasomal chymotrypsin-like activity assay and polyubiquitinated protein accumulation；Interaction with the proteasomal β5 subunit in a conformation suitable for proteasome inhibition; increase of caspase-3 activation. Yang et al. (2008)
LNCaP
C4-2B
Phenethyl-Isothiocyanat(PEITC) (114) Isothiocyan-ates Distributed in various plants C4-2B In vitro Antiproliferation Increase in the G2-M phase; downregulate AR expression through inhibition of the transcription factor Sp1 and p300/CBP-associated factor (PCAF); upregulation of miR-194 via directly targeting BMP1, and downregulation of BMP1 led to decrease expression of key oncogenic matrix metalloproteinase, MMP2 and MMP9. Wang et al. (2006), Yin et al. (2009), Jiang et al. (2013), Zhang et al. (2016)
DU145 LNCaP PC3 In vivo Induction of apoptosis
Putrescine-1,4-dicinnamide (115) Phenylprop-anoids Distributed in various plants DU145 In vitro Induction of apoptosis Increase the caspase-3 activity; increase of ROS generation. Russo et al. (2007)
Physalins A(116) Secosteriods Physalisalkekengi var. franchetii C4-2B 22Rv1 In vitro Antiproliferation Induction of apoptosis Inhibition of JNK and ERK activation; downregulation of AR expression and PAS expression. Han et al. (2011)
Physalins B (117) Secosteriods Physalisalkekengi var. franchetii C4-2B 22Rv1 In vitro Antiproliferation Inhibition of JNK and ERK activation; downregulation of AR expression and PAS expression. Han et al. (2011)
Induction of apoptosis
Physachenolide C (118) Steroids Disbributed in various plants LNCaP PC3 In vitro Cytotoxicity Inhibition of tumor cell growth Not investigated. Xu et al. (2015)
In vivo
Reevesioside A (119) Glycosides Reevesia formosana DU145 PC3 In vitro Antiproliferation Induction of apoptosis Induction of G1 cell cycle arrest by the downregulation of several related cell cycle regulators, including cyclin D1, cyclin E and CDC25A; increase of association between RB and E2F1 and the subsequent suppression of E2F1 activity via decreasing RB phosphorylation. Leu et al. (2014)
Scopoletin(120) Coumarins Erycibe obtusifolia LNCaP In vitro Antiproliferation Induction of G2/M cell cycle arrest by the downregulation of cyclin D1 expression. Li et al. (2015a)
Induction of apoptosis
Sulforaphane(SNF) (121) Sulfides Disbributed in various plants TRAMP C1 In vitro Anti-oxidation Regulation of Nrf2’s CpGs demethylation and reactivation. Zhang et al. (2013)
In vivo
Thymoquinone (122) Quinones Nigella sativa C2-2B In vitro Induction of apoptosis Not investigated. Trang et al. (1993)
DU145
LNCaP PC3
Wedelolactone(123) Esters Wedelia sinensis DU145 PrEC PC3 In vitro Induction of apoptosis Increase of c-JNK and caspase-3 activity by downregulation of PKCε without AKT inhibition. Koka et al. (2010), Sarveswaran et al. (2012)
LNCaP
Z-Ligustilide(124) Esters Angelica sinensis (Oliv.) Diels TRAMP C1 In vitro Cytotoxicity Increase of Nrf2 expression via the Nrf2 promoter CpGs demethylation. Su et al. (2013)
2,5-dimethylphenol(125) Phenols Chlaenius cordicolli PC3 In vitro Cytotoxicity Induction of [Ca2+]i rise through PKC-regulated store-operated Ca2+ channels and PLC- dependent Ca2+ release from the endoplasmic reticulum. Wang et al. (2016a)
3-oxo-tirucallic acid(126) Lupanic acids Boswellia carteri Birdw. LNCaP PC3 In vitro Induction of apoptosis Inhibition of tumor cell growth Inhibition of Akt activity and Akt signaling pathways, including glycogen synthase kinase-3β and BAD phosphorylation, and nuclear accumulation of p65, androgen receptor, β-catenin, and c-Myc. Estrada et al. (2010)
In vivo
3-α-acetoxy-tirucallic acid(127) Lupanic acids Boswellia carteri Birdw. LNCaP PC3 In vitro Induction of apoptosis Inhibition of tumor cell growth Inhibition of Akt activity and Akt signaling pathways, including glycogen synthase kinase-3β and BAD phosphorylation, and nuclear accumulation of p65, androgen receptor, β-catenin, and c-Myc. Estrada et al. (2010)
In vivo
3-β-acetoxy-tirucallic acid(128) Lupanic acids Boswellia carteri Birdw. LNCaP PC3 In vitro Induction of apoptosis Inhibition of tumor cell growth Inhibition of Akt activity and Akt signaling pathways, including glycogen synthase kinase-3β and BAD phosphorylation, and nuclear accumulation of p65, androgen receptor, β-catenin, and c-Myc. Estrada et al. (2010)
In vivo
6α-acetoxyanopterine(129) Esters Anopterus macleayanus LNCaP In vitro Antiproliferation Interaction with tubulin. Levrier et al. (2016)
PC3 Induction of apoptosis
24-epibrassinolide(130) Brassinoste-roids Distributed in various plants DU145 LNCaP In vitro Antiproliferation; Induction of G1 cell cycle arrest accompanied by reductions in cyclin D1, CDK4/6 and pRb expression in LNCaP cells; induction of G2/M cell cycle arrest by reductions in cyclin A, cyclin expression in DU145 cells. Steigerova et al. (2012)
In vivo Induction of apoptosis
25-OH-PPD (131) Saponins Panax ginseng C.A.Mey. LNCaP PC3 In vitro Antiproliferation Induction of G1 cell cycle arrest by downregulation of MDM2, E2F1, Bcl2, cdk2/4/6, and cyclin D1 expressions; increase of p21, p27, and Bax expressions; induction of PARP cleavage and caspases activation. Wang et al. (2008a)
Induction of apoptosis
In vivo Inhibition of tumor growth
28-homocastasterone(132) Brassinosteroids Distributed in various plants DU145 LNCaP In vitro Antiproliferation; Induction of G1 cell cycle arrest accompanied by reductions in cyclin D1, CDK4/6 and pRb expression in LNCaP cells; induction of G2/M cell cycle arrest via reductions in cyclin A expression. Steigerova et al. (2012)
In vivo Induction of apoptosis
2′- Hydroxycinnamaldehyde (133) Aldehydes Cinnamomum verum J.Presl DU145; LNCaP In vitro Antiproliferation;Induction of apoptosis Signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation Yoon et al. (2019)
In vivo
Methyllucidone (134) cyclopentenedione Lindera erythrocarpa Makino (Lauraceae) DU145 In vitro Inhibition of cell growth; Induction of apoptosis Arrest of the cell cycle at G1 phase;regulation of the expression of the protein tyrosine phosphatase MEG2 Jin et al. (2018)
Ophiopogonin D＇(135) triterpenoid saponins Radix Ophiopogonis PC3 ； DU145 In vitro Induction of apoptosis Via a RIPK1-related pathway Lu et al. (2018)
In vivo
Corchorusoside C(136) steroid Streptocaulon juventas (Lour.) Merr. (Apocynaceae) DU-145 In vitro Induction of apoptosis Inhibition of activity and protein expression of NF-κB (p50 and p65), IKK(α and β), and ICAM-1;decrease of protein expression of Bcl-2 and increase of expression of PARP-1;increase of caspases 3 and 7 Anaya-Eugenio et al. (2019a)
In vivo
Daucosterol (137) steroid saponin Crateva adansonii DC (Capparaceae) LNCaP;DU145;PC3 In vitro Antiproliferation;inhibition of cell growth;Induction of apoptosis Downregulation of cell cycle proteins (cdk1, pcdk1, cyclin A and B) in DU145 and PC3 cells;downregulation of cdk2 in PC3 cells;downregulation of Akt, pAKT 18 and Bcl-2 proteins;up-regulation of Bax Zingue et al. (2019)
Cyanidin 3-glucoside (138) Glycosides The dark purple glutinous rice (Oryza sativa L.) cultivar Luem Pua (LP) PC3 In vitro Inhibition of progressive cancer cell behaviors Inhibit EMT through Smad signaling pathway(s) mediating Snail/E-cadherin expression Jongsomchai et al. (2020)
Germacrone (139) Ketones Rhizoma Curcuma PC-3;22RV1 In vitro Antiproliferation;Induction of apoptosis Inhibiting the Akt/mTOR signaling pathway Yu et al. (2020)
Ineupatolide (140) Esters Carpesium cernuum L. PC-3 In vitro Antiproliferation Promoting apoptosis and arresting the cell cycle in the G2and S phases; Huang et al. (2021)
Jegosaponin A and B (141 and 142) Saponins Styrax japonica Siebold et al. Zuccarini. PC-3 In vitro Exhibiting cell membrane disruptive properties Not investigated Nishimura et al. (2021)
In vivo
Isolobetyol (143) polyacetylene Platycodon grandiflorus (Jacq.) A.DC. PC-3 In vitro Antiproliferation Not investigated Li, (2020)
Lobetyol (144) Alkynes Platycodon grandiflorus (Jacq.) A.DC. PC-3 In vitro Antiproliferation Not investigated Li, (2020)
Lobetyolin (145) Alkynosides Platycodon grandiflorus (Jacq.) A.DC. PC-3 In vitro Antiproliferation Not investigated Li, (2020)
Extracts With Anti-Prostate Cancer Activity

Extracts consist of a group of bioactive natural compounds, which may exert and possess the advantages of synergistic effects against diseases. Recently, nutraceuticals have also received increasing attention as the agents or dietary supplements for cancer prevention and treatment, as well as some extracts derived from edible sources. Thus in this section we will respectively review those extracts and nutraceuticals that have the potential effects against prostate cancer either in vitro or in prostate cancer mice models. Chinese herbal compound preparations of more than one medicinal plants that have been reported to inhibit prostate cancer are also presented in this review.

Herbal Extracts

Traditional and folk herbal medicines from medicinal plants offer great potential for the discovery of novel anti-prostate cancer drugs. The plant extracts listed in Table 8 are complex mixtures, which need further investigations to reveal their bioative constituents through bioguided isolation and to clarify the roles of these different compounds in agaisnt prostate cancer when used alone or in combination. Also, the synergistic effect of the individual active components of these extracts and molecular mechanisms involved need further elucidation in order to evaluate the potential of these compounds as antineoplastic agents.

Extracts obtained from plants with anti-prostate cancer activities.

Extract Botanical name Medicinal part Cell type Observation Activity Mechanism of action Refs
Ethanol extract Vitex negundo L. Seed PC3 In vitro Antiproliferation Induction of cleavage in poly ADP ribose polymerase protein; upregulation of Bax and downregulation of Bcl-2; increase of caspase-3 and -9. Zhou et al. (2009)
In vivo
Methanolic extract Aloe perryi Baker Fruit HTB-81 In vitro Induction of apoptosis Not investigated. Al-Oqail et al. (2016)
Ethanolic extract Annona muricata L. Leaf PC3 In vitro Antiproliferation Not investigated. Yang et al. (2015)
In vivo Inhibition of tumor growth
Aqueous extract Camellia sinensis (L.) Kuntze Leaf PC3 In vitro Antiproliferation Increase of Bax/Bcl-2 ratio and decrease of Ki67 protein expression; decrease of blood concentrations of tumor growth factors and tumor concentrations of VEGF and EGF expressions. Wang et al. (2016b)
In vivo Induction of apoptosis Inhibition of tumor growth
Methanolic extract Artocarpus altilis (Parkinson) Fosberg Leaf and stem DU145 LNCap PC3 In vitro Antiproliferation Inhibition of STAT3 Ty705 phosphorylation and STAT3 activation. Jeon et al. (2015a)
Induction of apoptosis
In vivo Inhibition of tumor growth
Hexane extract Juglans regia L. Leaf PC3 In vitro Antiproliferation Not investigated. Li et al. (2015b)
Induction of apoptosis
Ammonia dichloromethane extract Berberis libanotica Root DU145 PC3 22Rv1 In vitro Antiproliferation Induction of G0/G1 cell cycle arrest; eradication of self-renewal ability of highly resistant prostate cancer stem cells.
Inhibition of metastasis
Supercritical extract Azadirachta indica A.Juss. Leaf LNCaP PC3 In vitro Antiproliferation Inhibition of calreticulin, integrin b1, and focal adhesion kinase activation; increase of the AKR1C2 level. Wu et al. (2014)
In vivo Induction of apoptosis Inhibition of tumor growth
Acetone extract Chaenomeles japonica (Thunb.) Lindl. ex Spach Fruit PNT1A PC3 In vitro Induction of apoptosis Increase of Bax/Bcl-2 ration. Lewandowska et al. (2013)
Hexanic lipidosterolic extract Serenoa repens (W.Bartram) Small Whole plant LNCaP PC3 In vitro Induction of apoptosis Increase of caspase 9 activation and poly (ADP-ribose) polymerase 1 cleavage, and mitochondrial PTP activation. Baron et al. (2009)
Aqueous extract Taraxacum officinale F.H.Wigg. Root C4-2B LNCaP In vitro Inhibition of metastasis Decrease of phosphorylation levels of FAK and SRC, and activities of matrix metalloproteinases (MMP-2 and MMP-9). Sigstedt et al. (2008)
Ethyl acetate extract Commiphora mukul (Hook. ex Stocks) Engl. Bark LNCaP PrEC In vitro Induction of apoptosis Decrease of Bax expression; suppression of JNK activation. Xiao et al. (2011)
Aqueous extract Cistus creticus L. ； Cistus monspeliensis L. Whole plant PZ-HPV-7 PNT1A In vitro Antiproliferation Not investigated. Vitali et al. (2011)
Acidified dimethyl sulfoxide extract Morus nigra L. Fruit PC3 CRL1435 In vitro Antiproliferation Induction of G1 cell cycle arrest; decrease mitochondrial membrane potential. Turan et al. (2017)
Induction of apoptosis
Dichloromethane extract Strobilanthes crispa (L.) Blume Leaf DU145 PC3 In vitro Induction of apoptosis Increase of caspase 3 and/or 7 activity. Visweswaran et al. (2010)
Punica granatum exeract Punica granatum L. Seed LNCaP PC3 In vitro Induction of apoptosis Inbition of metastasis Upregulation of p21 and p27; increase of JNK phosphorylation; suppression of AKT/mTOR signaling; modulation of the IGF-IGFBP axis. Deng et al. (2017)
Hydroalcoholic extract Justicia spicigera Schltdl. stems; LNCaP In vitro Antiproliferation cytostatic mechanism Fernández-Pomares et al. (2017)
leaves
Ethyl acetate fraction Phoenix dactylifera L. (Ajwa dates) Fruit PC3 In vitro Induction of apoptosis Arrest of the cell cycle in S phase Mirza et al. (2018)
Ethyl acetate extract Kalanchoe flammea Stapf (Crassulaceae) Leaves PC-3; In vitro; Induction of apoptosis Phosphatidylserine translocation; overproduction of reactive oxygen species;release of Cytochrome C at mitochondrial level; activation of caspase-3 and -9;downregulation of apoptosis-related proteins Bcl-2, XIAP, and PKCε and DNA fragmentation and cell cycle arrest Arias-González et al. (2018)
LNCaP;
PrEC In vivo
Hydroalcoholic extracts Euphorbia szovitsii Fisch. & C.A.Mey., U. dioica and Medicago sativa L. aerial parts PC-3, DU145 ； HDF In vitro Antiproliferation Not investigated Asadi-Samani et al. (2018)
Ethanol extract Moringa oleifera flower flower PC-3 In vitro Induction of Apoptosis Downregulation of AKT Pathway Ju et al. (2018)
methanolic extract Paederia foetida L. leaves PC-3, DU-145,HaCaT In vitro Inhibition of cell growth, migration; induction of apoptosis Modulating chromatin modification enzymes and altering pro-inflammatory cytokine gene expression Pradhan et al. (2019)
Ethanolic extract Moringa peregrina (Forssk.) Fiori seed PC-3 In vitro Induction of apoptosis Cell cycle arrest at sub-G0 phase and DNA fragmentation. Abou-Hashem et al. (2019)
Ethanolic extract dandelion (Taraxacum officinale) root and lemongrass (Cymbopogon citratus) Root In vivo Induction of apoptosis Not investigated Nguyen et al. (2019)
Ethanolic extract Glycyrrhiza glabra (Fabaceae family) roots PC-3 In vitro Antiproliferation Both apoptosis and autophagy mechanisms Gioti et al. (2020)
Dimethyl sulfoxide extract Ganoderma lucidum whole plant PC3 In vitro Induction of apoptosis Inhibition of Jak-1/STAT-3 activity Wang et al. (2020)
Methanolic extract Moringa oleifera Lam. leaf DU145;PC-3 In vitro Antiproliferation; induction of apoptosis;G0/G1 cell cycle arrest Downregulation of Notch signaling；downregulation of Hedgehog Signaling Pathway (Khan et al., 2020a; Khan et al., 2020b)
Dichloromethane and methanol extract Cecropia pachystachya Trécul leaves PC3 In vitro Senescence induction β-galactosidase overexpression Rosa et al. (2020)
Methanolic extract Dracocephalum palmatum Stephan leaves PC-3 In vitro Induction of apoptosis Via the caspase-8-mediated extrinsic pathway Lee et al. (2020)
Extract of multi-solvent systems(Cyclohexane, Hexane, Diethyl Ether, Ethyl Acetate, Methanol, Water) Hippophae rhamnoides L. and Hippophae tibetana Schltdl. leaves LNCaP;C4-2 In vitro Antiproliferation Downregulation of androgen responsive genes, PSA, ELL2, EAF2 and CALR Masoodi et al. (2020)
Ethanolic extract Salvia miltiorrhiza Bunge. roots DU-145 In vitro; Antiproliferation;induction of apoptosis; Increase of the expression of p53 and reducion of the expression of Bcl-2 proteins Bae et al. (2020)
In vivo
Ethanolic extract Spirogyra neglecta (Hassall) Kutzing whole plant PC3 In vitro Antimetastasis activity Inhibiting the Akt signaling pathway Arjsri et al. (2021)
Methanolic extract Artemisia kruhsiana subsp. alaskana (Rydb.) D.F.Murray & Elven stems and leaves PC-3 In vitro Induction of autophagy; Inhibitions of phosphor (p)-AKT, p-mTOR, Bcl-2, and Bax, activating beclin 1 and LC3 ratio in PC-3 cells Lee et al. (2021)
Ethanolic extracts Treculia africana Decne. (Moraceae) and Entandrophragma angolense Welw (Meliaceae) whole plants LNCaP, DU145 and PC3 In vitro Antiproliferation;induction of apoptosis; anti-metastatic effects Overexpression of caspase-3; low expression of Akt, pAkt and Bcl-2 proteins;a decrease of chemotaxis and cell migration Zingue et al. (2021)
Ethanolic extracts Moringa oleifera Lam. Flower PC-3 In vitro Induction of apoptosis Downregulation of AKT Pathway Ju et al. (2018)
Chinese Herbal Compound Preparations

There are four traditional Chinese medical formulations reported to display significant anti-prostate cancer properties, that is, Zyflamend, PC-SPES and LCS101, which are composed of different medicinal plants (Table 9; Bemis et al., 2005; Hsieh et al., 1997; Cohen et al., 2015). Especially, PC-SPES significantly inhibited prostate tumor growth in tumor-bearing mouse model, mainly through cell cycle arrest and apoptosis induction, which is already clinically utilized for the treatment of clincal patients with prostate cancer (Hsieh et al., 1997).

Chinese herbal compound preparations obtained from plants with anti-prostate cancer activities.

Medical formulation Composition Cell type Observation Activity Mechanism of action Refs
Zyflamend Rosemary; Ginger; Turmeric; Green tea; Holy basil; Hu zhang; Chinese goldthread; LNCaP In vitro Antiproliferation Inhibition of COX-1 and COX-2 enzyme activities; upregulation of p21 expression; downregulation of AR expression; induction of phosphorylation of Stat3 and PKCα/β. Bemis et al. (2005)
Oregano; Barberry;
Scutellaria baicalensis. Induction of apoptosis
PC-SPES Ganoderma lucidium; DU145 In vitro Induction of apoptosis Induction of G0/G1 and G2/M cell cycle arrest; upregulation of p21waf1 expression and downregulation of Bcl-2 expression. Hsieh et al. (1997)
Dendranthema morifolium; Isatis indigotica; Glycyrrhiza glabra; Rabdosia rubescens; Panax pseudoginseng; Serenoa repens; Scutellaria baicalensis;. LNCaP In vivo Inhibition of tumor growth
PC3
LCS101 Atractylodes macrocephala; Astragalus membranaceus; Glehnia littoralis; Citrus reticulate; Lycium chinense; Ligustrum lucidum; Oldenlandia diffusa; Milletia reticulata; Ophiopogon japonicus; Paeonia obovata; Paeonia lactiflora; Prunella vulgaris; Poriae cocos; Scutellaria barbata. DU145 In vitro Induction of apoptosis Not investigated Cohen et al. (2015)
PC3
Nutraceuticals and Extracts Derived From Edible Sources

Nowadays, dietary factors play an increasingly important role in the chemopreventive and/or therapeutic management of cancer (Table 10). The study of dietary agents (nutraceuticals or extracts derived from edible sources) in prostate cancer prevention is an important area of research since about 43–80% patients with prostate cancer are on alternative therapy based on dietary modification (Lippert et al., 1999; Nam et al., 1999). There are strong evidences that nutraceuticals and extracts derived from edible spices, vegetables or fruits such as vitamin D, pomegranate and tea polyphenols have demonstrated significant anti-prostate cancer activity when tested either in vitro and/or in vivo (Kasimsetty et al., 2009; Gregory et al., 2010; Koyama et al., 2010; Mordanmccombs et al., 2010; Hsu et al., 2011; Xiao et al., 2011; Turan et al., 2017). Especially, dietary phytochemicals that can selectively interfere cellular pathways involved in prostate cancer cells have attracted research interest of scientists in prostate cancer therapies in recent years.

Nutraceuticals and extracts obtained from plants with anti-prostate cancer activities.

Dietary agents Cell type Observation Activity Mechanism of action Refs
Epigallocatechin-3-Gallate (Green Tea) Du145 In vivo Antiproliferation Downregulation of ID2; increase of Bax/Bcl-2; inducing cell death via an ID2-related mechanism; Antiproliferation by increasing the activity of ERK 1/2 through a MEK-independent and PI3K-dependent mechanism. Xiao et al. (2011), Turan et al. (2017)
LNCaP In vitro Induction of apoptosis
Grape skin C4-2B LNCaP ARCaP-E In vitro Induction of apoptosis Inhibition of metastasis Decrease of nail and pSTAT3 expression; inhibition of Snail-mediated CatL activity. Burton et al. (2015)
In vivo
Modified Citrus Pectin LNCaP PC3 In vivo Induction of apoptosis Cell growth inhibition and apoptosis induction via inhibiting MAPK/ERK signaling pathway and activating caspase 3. Azémar et al. (2007), Yan and Katz (2010)
In vitro
ProstaCaid PC3 In vitro Antiproliferation Downregulation of expression CCND1, CDK4, E2F1and MAPK6; upregulation of CDKN1A expression; downregulation of CAV1, IGF2, NR2F1, and PLAU genes expression; suppression of the urokinase plasminogen activator (uPA) secretion. Jiang et al. (2011)
Inhibition of and migration invasion
Pomegranate C4-2B In vitro Antiproliferation Inhibition of enzyme (cytochrome P450) expression and activity; inhibition of mTOR phosphorylation at Ser2448 and Ser2481 and IGF1 expression. Malik et al. (2005), Hong et al. (2008), Kasimsetty et al., (2009), Koyama et al. (2010)
DU145
LNCaP
LNCaP-AR In vivo Induction of apoptosis Inhibition of metastasis
PC3
22Rv1
Selenium C4-2B LNCaP PC3 In vitro Antiproliferation Increase of p53 expression; apoptosis induction by superoxide generation through the mitochondrial-dependent pathway Pinto et al. (2007), Xiang et al. (2009), Sarveswaran et al. (2010)
In vivo Induction of apoptosis
Soy LNCaP In vitro Antiproliferation Decreased of COX-2 RNA and protein expression; inhibition of the synthesis of prostaglandins; downregulation growth factors involved in angiogenesis (EGF and IGF-1) and the IL-8 gene; inhibition of ERK-1 and ERK-2 expression. Wang et al. (2004), Swami et al. (2009), Rabiau et al. (2010)
PC3 In vivo Inhibition of tumor growth
Vitamin D DU145 LNCaP PC3 In vitro Antiproliferation Increase of E-cadherin expression; decrease of urokinase plasminogen activator receptor levels. Gregory et al. (2010), Mordanmccombs et al. (2010), Hsu et al. (2011)
In vivo Inhibition of migration
Vitamin K2 VCaP in vitro Antiproliferation;Induction of apoptosis Downregulation of the expression of androgen receptor, BiP, survivin, while activating caspase-3 and -7, PARP-1 cleavage, p21 and DNA damage response marker, phospho-H2AX Dasari et al. (2018)
Algerian propolis LNCaP in vitro Induction of apoptosis Blocking the cell cycle at G0/G1 phase. Zabaiou et al. (2019)
Conclusion and Perspectives

Prostate cancer is the second most frequently diagnosed tumor and the fifth leading cause of cancer-related deaths in men in the worldwide (McEleny et al., 2002). And the mortality of prostate cancer mainly occurs as a result of the castrate resistant ones. Up to date, different kinds of drugs have been employed to improve the treatment condition, mainly including LHRH antagonists, antiandrogen (androgen receptor antagonists and androgen synthesis inhibitors), tyrosine kinase inhibitors, angiogenesis inhibitors, endothelin antagonists, matrix metalloproteinase inhibitors, antioxidants, and cell cycle inhibitors. However, as mentioned above, there is no effective therapy for CRPC at present, except for docetaxel, which is the only chemotherapeutic agent that has been proven to prolong the overall survival in CRPC patient population though with many adverse effects reported (Eyben et al., 2015). Hence, it is urgent for us to explore an effective treatment for prostate cancer, especially for CRPC. In recent years, many natural products and extracts have been scientifically investigated in vitro and/or in vivo and proved as potential anti-prostate cancer agents, which are currently scattered across various publications. So a systematic summary and knowledge of future prospects are necessary to facilitate further chemical and pharmacological studies for anti-prostate cancer agents.

In our review, we provided a comprehensive overview of the molecular basis of the incidence and development of prostate cancer, especially for castration-resistant prostate cancer (CRPC), which mainly including canonical AR signaling (AR amplification, over-expression, mutation, and unconventional activation), and non-nuclear AR signaling (PI3K/AKT, Src, MAPKs, JAK-STAT3, and Ca2+ signaling pathways). So most components involved in above-mentioned pathways represent potential targets for screening natural compounds and/or extracts with anti-prostate cancer activity. And natural compounds or extracts that could function as modulators of canonical AR or non-nuclear AR signalling pathways thus can be regarded as promising candidates for anti-prostate interventions.

So far, a great amount of natural products isolated from diverse sources have been found to significantly inhibit prostate cancer cell proliferation/tumor growth or affected cellular signaling pathways in prostate cancer. As shown in our paper, the majority of natural compounds with direct relevance to prostate cancer are primarily derived from plants, with comparatively few molecules from marine and microbial sources. For these reported bioactive constituents, there is still plenty of room for improvement regarding the studies focused on efficacy enhancement and side effects amelioration by semi-synthetic modifications based on quantitative structural activity relationship elucidation. Since marine and microbial organisms represent important sources for single molecules exploit, more available and improved approaches should be included in finding novel natural products with significant anti-prostate cancer activity from these resource. Especially, engineering bacteria or fungus with novel gene clusters, currently used mainly for the identification of antibiotics or anti-tumor drugs, would be another promising approach for discovering natural compounds with anti-prostate activity. Extracts are another applicable option for anti-prostate purposes, in which case the chemical profile should be further elucidated, possibly affording a pure bioactive compound with precise mechanism of action. Also clinically used Chinese herb preparations should be profiled using techniques such as HPLC–MS to standardize the complex system to make it more controllable, stable, and reproducible in prostate cancer treatment. Furthermore, drug combination of these reported natural compounds with conventional chemotherapeutic agents may also be a promising way in finding solution for prostate cancer treatment. Finally, safty large-scale studies are needed to evaluate promising compounds or extracts and determing non-toxic doses for treating prostate cancer in mammals.

In conclusion, tackling prostate cancer (especially CRPC) is a much needed task that requires not only the great progress in understanding the genetic basis of prostate cancer, but also the significant technological improvements in tracking of bioactive natural compounds and structural characterization, which will facilitate the identification of novel natural compounds with significant anti-prostate cancer properties for drug development and therefore can be translated into significant health benefits for humans.

 Author Contributions

CZ, WX, and QY conceived and designed the outline of the manuscript; BB, QC, and RJ collated and summarized the literatures; XQ, HW and YB analyzed the data; RJ, BB, and CZ wrote the manuscript, QC, WX, and QY revised the manuscript and provided technical assistance to RJ and BB.

 Funding

The work was supported by the National Nature Science Foundation of China (No. 82174081, 81770604), the Program of Shanghai Health System Subject Chief Scientist (2017BR004), and Shanghai Natural Science Fund (21ZR1478000).

 Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 References Aalinkeel R. Bindukumar B. Reynolds J. L. Sykes D. E. Mahajan S. D. Chadha K. C. (2008). The Dietary Bioflavonoid, Quercetin, Selectively Induces Apoptosis of Prostate Cancer Cells by Down-Regulating the Expression of Heat Shock Protein 90. Prostate 68 (16), 1773–1789. 10.1002/pros.20845 Abeshouse A. Ahn J. Akbani R. Ally A. Amin S. Andry C. D. (2015). The Molecular Taxonomy of Primary Prostate Cancer. Cell 163 (4), 1011–1025. 10.1016/j.cell.2015.10.025 Abou-Hashem M. M. M. Abo-Elmatty D. M. Mesbah N. M. Abd El-Mawgoud A. M. (2019). Induction of Sub-G0 Arrest and Apoptosis by Seed Extract of Moringa Peregrina (Forssk.) Fiori in Cervical and Prostate Cancer Cell Lines. J. Integr. Med. 17 (6), 410–422. 10.1016/j.joim.2019.09.004 Acquaviva R. Di Giacomo C. Sorrenti V. Galvano F. Santangelo R. Cardile V. (2012). Antiproliferative Effect of Oleuropein in Prostate Cell Lines. Int. J. Oncol. 41 (1), 31–38. 10.3892/ijo.2012.1428 Acuña U. M. Mo S. Zi J. Orjala J. DE Blanco E. J. C. (2018). Hapalindole H Induces Apoptosis as an Inhibitor of NF-ĸb and Affects the Intrinsic Mitochondrial Pathway in PC-3 Androgen-Insensitive Prostate Cancer Cells. Anticancer Res. 38 (6), 3299–3307. 10.21873/anticanres.12595 Afaq F. Zaman N. Khan N. Syed D. N. Sarfaraz S. Zaid M. A. (2008). Inhibition of Epidermal Growth Factor Receptor Signaling Pathway by Delphinidin, an Anthocyanidin in Pigmented Fruits and Vegetables. Int. J. Cancer 123 (7), 1508–1515. 10.1002/ijc.23675 Al-Oqail M. M. El-Shaibany A. Al-Jassas E. Al-Sheddi E. S. Al-Massarani S. M. Farshori N. N. (2016). In Vitro anti-proliferative Activities of Aloe Perryi Flowers Extract on Human Liver, colon, Breast, Lung, Prostate and Epithelial Cancer Cell Lines. Pak J. Pharm. Sci. 29 (2 Suppl. l), 723–729. Anaya-Eugenio G. D. Addo E. M. Ezzone N. Henkin J. M. Ninh T. N. Ren Y. (2019a). Caspase-Dependent Apoptosis in Prostate Cancer Cells and Zebrafish by Corchorusoside C from Streptocaulon Juventas. J. Nat. Prod. 82 (6), 1645–1655. 10.1021/acs.jnatprod.9b00140 Anaya-Eugenio G. D. Rebollar-Ramos D. González M. D. C. Raja H. Mata R. Carcache de Blanco E. J. (2019b). Apoptotic Activity of Xanthoquinodin JBIR-99, from Parengyodontium Album MEXU 30054, in PC-3 Human Prostate Cancer Cells. Chem. Biol. Interact 311, 108798. 10.1016/j.cbi.2019.108798 Arias-González I. García-Carrancá A. M. Cornejo-Garrido J. Ordaz-Pichardo C. (2018). Cytotoxic Effect of Kalanchoe Flammea and Induction of Intrinsic Mitochondrial Apoptotic Signaling in Prostate Cancer Cells. J. Ethnopharmacol 222, 133–147. 10.1016/j.jep.2018.04.038 Arjsri P. Phetcharaburanin J. Suksawat M. Mapoung S. Subkamkaew C. Semmarath W. (2021). Spirogyra Neglecta (Hassall) Kützing Attenuates Metastasis of Castration-Resistant Human Prostate Cancer via the Blockage of AKT Signaling Pathway. South Afr. J. Bot. 139 (Suppl. 10), 26–37. 10.1016/j.sajb.2021.02.005 Arora N. Kumar S. Satti N. K. Ali A. Gupta P. Katoch M. (2018). A Strain of Streptomyces Sp. Isolated from Rhizospheric Soil of Crataegus Oxycantha Producing Nalidixic Acid, a Synthetic Antibiotic. J. Appl. Microbiol. 124 (6), 1393–1400. 10.1111/jam.13736 Arulselvan P. Ju J. Gothai S. Hasanpourghadi M. Nasser A. Aziz Ibrahim I. (2018). Anticancer Potential of Moringa Oleifera Flower Extract in Human Prostate Cancer PC-3 Cells via Induction of Apoptosis and Downregulation of AKT Pathway. Phcog Mag. 14 (58), 477. 10.4103/pm.pm_516_17 Asadi-Samani M. Rafieian-Kopaei M. Lorigooini Z. Shirzad H. (2018). A Screening of Growth Inhibitory Activity of Iranian Medicinal Plants on Prostate Cancer Cell Lines. Biomedicine (Taipei) 8 (2), 8. 10.1051/bmdcn/2018080208 Asea A. Ara G. Teicher B. A. Stevenson M. A. Calderwood S. K. (2001). Effects of the Flavonoid Drug Quercetin on the Response of Human Prostate Tumours to Hyperthermia In Vitro and In Vivo . Int. J. Hyperthermia 17 (4), 347–356. 10.1080/02656730110053146 Asim M. Siddiqui I. A. Hafeez B. B. Baniahmad A. Mukhtar H. (2008). Src Kinase Potentiates Androgen Receptor Transactivation Function and Invasion of Androgen-independent Prostate Cancer C4-2 Cells. Oncogene 27 (25), 3596–3604. 10.1038/sj.onc.1211016 Auchus R. J. (2004). The Backdoor Pathway to Dihydrotestosterone. Trends Endocrinol. Metab. 15 (9), 432–438. 10.1016/j.tem.2004.09.004 Azémar M. Hildenbrand B. Haering B. Heim M. E. Unger C. (2007). Clinical Benefit in Patients with Advanced Solid Tumors Treated with Modified Citrus Pectin: A Prospective Pilot Study. Clin. Med. Oncol. 1 (1), CMO.S285–80. 10.4137/CMO.S285 Bae W. J. Choi J. B. Kim K. S. Ha U. S. Hong S. H. Lee J. Y. (2020). Inhibition of Proliferation of Prostate Cancer Cell Line DU-145 In Vitro and In Vivo Using Salvia Miltiorrhiza Bunge. Chin. J. Integr. Med. 26 (7), 533–538. 10.1007/s11655-017-2801-5 Bao X. Zhu J. Ren C. Zhao A. Zhang M. Zhu Z. (2021). β-Elemonic Acid Inhibits Growth and Triggers Apoptosis in Human Castration-Resistant Prostate Cancer Cells through the Suppression of JAK2/STAT3/MCL-1 and NF-ĸb Signal Pathways. Chem. Biol. Interact 342, 109477. 10.1016/j.cbi.2021.109477 Barbieri C. E. Baca S. C. Lawrence M. S. Demichelis F. Blattner M. Theurillat J. P. (2012). Exome Sequencing Identifies Recurrent SPOP, FOXA1 and MED12 Mutations in Prostate Cancer. Nat. Genet. 44 (6), 685–689. 10.1038/ng.2279 Baron A. Mancini M. Caldwell E. Cabrelle A. Bernardi P. Pagano F. (2009). Serenoa Repens Extract Targets Mitochondria and Activates the Intrinsic Apoptotic Pathway in Human Prostate Cancer Cells. BJU Int. 103 (9), 1275–1283. 10.1111/j.1464-410X.2008.08266.x Belkina A. C. Denis G. V. (2012). BET Domain Co-regulators in Obesity, Inflammation and Cancer. Nat. Rev. Cancer 12 (7), 465–477. 10.1038/nrc3256 Beltran H. Prandi D. Mosquera J. M. Benelli M. Puca L. Cyrta J. (2016). Divergent Clonal Evolution of Castration-Resistant Neuroendocrine Prostate Cancer. Nat. Med. 22 (3), 298–305. 10.1038/nm.4045 Bemis D. L. Capodice J. L. Anastasiadis A. G. Katz A. E. Buttyan R. (2005). Zyflamend, a Unique Herbal Preparation with Nonselective COX Inhibitory Activity, Induces Apoptosis of Prostate Cancer Cells that Lack COX-2 Expression. Nutr. Cancer 52 (2), 202–212. 10.1207/s15327914nc5202_10 Ben-Eltriki M. Deb S. Adomat H. Tomlinson Guns E. S. (2016). Calcitriol and 20(S)-protopanaxadiol Synergistically Inhibit Growth and Induce Apoptosis in Human Prostate Cancer Cells. J. Steroid Biochem. Mol. Biol. 158, 207–219. 10.1016/j.jsbmb.2015.12.002 Bernemann C. Schnoeller T. J. Luedeke M. Steinestel K. Boegemann M. Schrader A. J. (2017). Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer. Eur. Urol. 71, 1–3. 10.1016/j.eururo.2016.07.021 Bodle C. R. Mackie D. I. Hayes M. P. Schamp J. H. Miller M. R. Henry M. D. (2017). Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines. J. Nat. Prod. 80 (7), 1992–2000. 10.1021/acs.jnatprod.7b00112 Bolli R. Dawn B. Xuan Y. T. (2003). Role of the JAK-STAT Pathway in protection against Myocardial Ischemia/reperfusion Injury. Trends Cardiovasc. Med. 13 (2), 72–79. 10.1016/s1050-1738(02)00230-x Bonham M. Posakony J. Coleman I. Montgomery B. Simon J. Nelson P. S. (2005). Characterization of Chemical Constituents in Scutellaria Baicalensis with Antiandrogenic and Growth-Inhibitory Activities toward Prostate Carcinoma. Clin. Cancer Res. 11 (10), 3905–3914. 10.1158/1078-0432.CCR-04-1974 Bowers Z. Caraballo D. Jebelli J. Famuyiwa T. Kumi-Diaka J. (2021). Therapeutic Potential of Pseudopterosin H on a Prostate Cancer Cell Line. FASEB 35. 10.1096/fasebj.2021.35.S1.04601 Bureyko T. Hurdle H. Metcalfe J. B. Clandinin M. T. Mazurak V. C. (2009). Reduced Growth and Integrin Expression of Prostate Cells Cultured with Lycopene, Vitamin E and Fish Oil In Vitro . Br. J. Nutr. 101 (7), 990–997. 10.1017/S0007114508051684 Burton L. J. Smith B. A. Smith B. N. Loyd Q. Nagappan P. McKeithen D. (2015). Muscadine Grape Skin Extract Can Antagonize Snail-Cathepsin L-Mediated Invasion, Migration and Osteoclastogenesis in Prostate and Breast Cancer Cells. Carcinogenesis 36 (9), 1019–1027. 10.1093/carcin/bgv084 Cai H. Smith D. A. Memarzadeh S. Lowell C. A. Cooper J. A. Witte O. N. (2011). Differential Transformation Capacity of Src Family Kinases during the Initiation of Prostate Cancer. Proc. Natl. Acad. Sci. U S A. 108 (16), 6579–6584. 10.1073/pnas.1103904108 Cary K. C. Cooperberg M. R. (2013). Biomarkers in Prostate Cancer Surveillance and Screening: Past, Present, and Future. Ther. Adv. Urol. 5 (6), 318–329. 10.1177/1756287213495915 Castro M. J. Careaga V. P. Sacca P. A. Faraoni M. B. Murray A. P. Calvo J. C. (2019). Lupane Triterpenoids and New Derivatives as Antiproliferative Agents against Prostate Cancer Cells. Anticancer Res. 39 (7), 3835–3845. 10.21873/anticanres.13533 Chan M. L. Liang J. W. Hsu L. C. Chang W. L. Lee S. S. Guh J. H. (2015). Zerumbone, a Ginger Sesquiterpene, Induces Apoptosis and Autophagy in Human Hormone-Refractory Prostate Cancers through Tubulin Binding and Crosstalk between Endoplasmic Reticulum Stress and Mitochondrial Insult. Naunyn Schmiedebergs Arch. Pharmacol. 388 (11), 1223–1236. 10.1007/s00210-015-1152-z Chang H. T. Chou C. T. Chen I. L. Liang W. Z. Kuo D. H. Huang J. K. (2013). Mechanisms of Resveratrol-Induced Changes in [Ca(2+)]i and Cell Viability in PC3 Human Prostate Cancer Cells. J. Recept Signal. Transduct Res. 33 (5), 298–303. 10.3109/10799893.2013.822886 Chang K. H. Li R. Papari-Zareei M. Watumull L. Zhao Y. D. Auchus R. J. (2011). Dihydrotestosterone Synthesis Bypasses Testosterone to Drive Castration-Resistant Prostate Cancer. Proc. Natl. Acad. Sci. U S A. 108 (33), 13728–13733. 10.1073/pnas.1107898108 Chang K. H. Sharifi N. (2012). Prostate Cancer-From Steroid Transformations to Clinical Translation. Nat. Rev. Urol. 9 (12), 721–724. 10.1038/nrurol.2012.175 Chaudhary A. Pechan T. Willett K. L. (2007). Differential Protein Expression of Peroxiredoxin I and II by Benzo(a)pyrene and Quercetin Treatment in 22Rv1 and PrEC Prostate Cell Lines. Toxicol. Appl. Pharmacol. 220 (2), 197–210. 10.1016/j.taap.2006.12.030 Chen C. D. Welsbie D. S. Tran C. Baek S. H. Chen R. Vessella R. (2004). Molecular Determinants of Resistance to Antiandrogen Therapy. Nat. Med. 10 (1), 33–39. 10.1038/nm972 Chen L. Yan F. Chen W. Zhao L. Zhang J. Lu Q. (2018). Procyanidin from Peanut Skin Induces Antiproliferative Effect in Human Prostate Carcinoma Cells DU145. Chem. Biol. Interact 288, 12–23. 10.1016/j.cbi.2018.04.008 Chen Y. C. Kung F. L. Tsai I. L. Chou T. H. Chen I. S. Guh J. H. (2010). Cryptocaryone, a Natural Dihydrochalcone, Induces Apoptosis in Human Androgen Independent Prostate Cancer Cells by Death Receptor Clustering in Lipid Raft and Nonraft Compartments. J. Urol. 183 (6), 2409–2418. 10.1016/j.juro.2010.01.065 Chiang Y. T. Wang K. Fazli L. Qi R. Z. Gleave M. E. Collins C. C. (2014). GATA2 as a Potential Metastasis-Driving Gene in Prostate Cancer. Oncotarget 5 (2), 451–461. 10.18632/oncotarget.1296 Chien C. S. Shen K. H. Huang J. S. Ko S. C. Shih Y. W. (2010). Antimetastatic Potential of Fisetin Involves Inactivation of the PI3K/Akt and JNK Signaling Pathways with Downregulation of MMP-2/9 Expressions in Prostate Cancer PC-3 Cells. Mol. Cel Biochem 333 (1-2), 169–180. 10.1007/s11010-009-0217-z Chintharlapalli S. Papineni S. Ramaiah S. K. Safe S. (2007). Betulinic Acid Inhibits Prostate Cancer Growth through Inhibition of Specificity Protein Transcription Factors. Cancer Res. 67 (6), 2816–2823. 10.1158/0008-5472.Can-06-3735 Cho H. D. Lee J. H. Moon K. D. Park K. H. Lee M. K. Seo K. I. (2018). Auriculasin-induced ROS Causes Prostate Cancer Cell Death via Induction of Apoptosis. Food Chem. Toxicol. 111, 660–669. 10.1016/j.fct.2017.12.007 Ciccarese C. Massari F. Iacovelli R. Fiorentino M. Montironi R. Di Nunno V. (2017). Prostate Cancer Heterogeneity: Discovering Novel Molecular Targets for Therapy. Cancer Treat. Rev. 54, 68–73. 10.1016/j.ctrv.2017.02.001 Cohen Z. Maimon Y. Yoeli-Lerner M. Yang P. Samuels N. Berger R. (2015). Selective Anticancer Effects and protection from Chemotherapy by the Botanical Compound LCS101: Implications for Cancer Treatment. Int. J. Oncol. 46 (1), 308–316. 10.3892/ijo.2014.2711 Colgate E. C. Miranda C. L. Stevens J. F. Bray T. M. Ho E. (2007). Xanthohumol, a Prenylflavonoid Derived from Hops Induces Apoptosis and Inhibits NF-kappaB Activation in Prostate Epithelial Cells. Cancer Lett. 246 (1-2), 201–209. 10.1016/j.canlet.2006.02.015 Cook K. M. Hilton S. T. Mecinovic J. Motherwell W. B. Figg W. D. Schofield C. J. (2009). Epidithiodiketopiperazines Block the Interaction between Hypoxia-Inducible Factor-1alpha (HIF-1alpha) and P300 by a Zinc Ejection Mechanism. J. Biol. Chem. 284 (39), 26831–26838. 10.1074/jbc.M109.009498 Courtney K. D. Corcoran R. B. Engelman J. A. (2010). The PI3K Pathway as Drug Target in Human Cancer. J. Clin. Oncol. 28 (6), 1075–1083. 10.1200/Jco.2009.25.3641 Coutinho I. Day T. K. Tilley W. D. Selth L. A. (2016). Androgen Receptor Signaling in Castration-Resistant Prostate Cancer: a Lesson in Persistence. Endocr. Relat. Cancer 23 (12), T179–T197. 10.1530/ERC-16-0422 Crawford N. P. Alsarraj J. Lukes L. Walker R. C. Officewala J. S. Yang H. H. (2008). Bromodomain 4 Activation Predicts Breast Cancer Survival. Proc. Natl. Acad. Sci. U S A. 105 (17), 6380–6385. 10.1073/pnas.0710331105 Dai W. Sun C. Huang S. Zhou Q. (2016). Carvacrol Suppresses Proliferation and Invasion in Human Oral Squamous Cell Carcinoma. Onco Targets Ther. 9, 2297–2304. 10.2147/ott.S98875 Dai X. Gan W. Li X. Wang S. Zhang W. Huang L. (2017). Prostate Cancer-Associated SPOP Mutations Confer Resistance to BET Inhibitors through Stabilization of BRD4. Nat. Med. 23 (9), 1063–1071. 10.1038/nm.4378 Dan R. Vanallen E. Wu Y. M. Schultz N. Lonigro R. Mosquera J. M. (2015). Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 161 (5), 1215. 10.1016/j.cell.2015.05.001 Dasari S. Samy A. L. P. A. Kajdacsy-Balla A. Bosland M. C. Munirathinam G. (2018). Vitamin K2, a Menaquinone Present in Dairy Products Targets Castration-Resistant Prostate Cancer Cell-Line by Activating Apoptosis Signaling. Food Chem. Toxicol. 115, 218–227. 10.1016/j.fct.2018.02.018 Davis J. E. Xie X. Guo J. Huang W. Chu W. M. Huang S. (2016). ARF1 Promotes Prostate Tumorigenesis via Targeting Oncogenic MAPK Signaling. Oncotarget 7 (26), 39834–39845. 10.18632/oncotarget.9405 Deepak M. Handa S. S. (2000). Antiinflammatory Activity and Chemical Composition of Extracts of Verbena Officinalis. Phytother Res. 14 (6), 463–465. 10.1002/1099-1573(200009)14:6<463::aid-ptr611>3.0.co;2-g Deng Y. Li Y. Yang F. Zeng A. Yang S. Luo Y. (2017). The Extract from Punica Granatum (Pomegranate) Peel Induces Apoptosis and Impairs Metastasis in Prostate Cancer Cells. Biomed. Pharmacother. 93, 976–984. 10.1016/j.biopha.2017.07.008 Destaing O. Block M. R. Planus E. Albiges-Rizo C. (2011). Invadosome Regulation by Adhesion Signaling. Curr. Opin. Cel Biol 23 (5), 597–606. 10.1016/j.ceb.2011.04.002 Ding W. Hu Z. Zhang Z. Ma Q. Tang H. Ma Z. (2015). Physapubescin B Exhibits Potent Activity against Human Prostate Cancer In Vitro and In Vivo . J. Agric. Food Chem. 63 (43), 9504–9512. 10.1021/acs.jafc.5b03045 Djusberg E. Jernberg E. Thysell E. Golovleva I. Lundberg P. Crnalic S. (2017). High Levels of the AR-V7 Splice Variant and Co-amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases. Prostate 77 (6), 625–638. 10.1002/pros.23307 Dyshlovoy S. A. Kudryashova E. K. Kaune M. Makarieva T. N. Shubina L. K. Busenbender T. (2020). Urupocidin C: a New marine Guanidine Alkaloid Which Selectively Kills Prostate Cancer Cells via Mitochondria Targeting. Sci. Rep. 10 (1), 9764. 10.1038/s41598-020-66428-5 Dyshlovoy S. A. Menchinskaya E. S. Venz S. Rast S. Amann K. Hauschild J. (2016). The marine Triterpene Glycoside Frondoside A Exhibits Activity In Vitro and In Vivo in Prostate Cancer. Int. J. Cancer 138 (10), 2450–2465. 10.1002/ijc.29977 Efstathiou E. Titus M. Tsavachidou D. Tzelepi V. Wen S. Hoang A. (2012). Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone. J. Clin. Oncol. 30 (6), 637–643. 10.1200/JCO.2010.33.7675 Erdogan S. Turkekul K. (2020). Neferine Inhibits Proliferation and Migration of Human Prostate Cancer Stem Cells through P38 MAPK/JNK Activation. J. Food Biochem. 44 (6). 10.1111/jfbc.13253 Eroğlu C. Avcı E. Vural H. Kurar E. (2018). Anticancer Mechanism of Sinapic Acid in PC-3 and LNCaP Human Prostate Cancer Cell Lines. Gene 671, 127–134. 10.1016/j.gene.2018.05.049 Estrada A. C. Syrovets T. Pitterle K. Lunov O. Büchele B. Schimana-Pfeifer J. (2010). Tirucallic Acids Are Novel Pleckstrin Homology Domain-dependent Akt Inhibitors Inducing Apoptosis in Prostate Cancer Cells. Mol. Pharmacol. 77 (3), 378–387. 10.1124/mol.109.060475 Fang Z. Zhang T. Dizeyi N. Chen S. Wang H. Swanson K. D. (2012). Androgen Receptor Enhances P27 Degradation in Prostate Cancer Cells through Rapid and Selective TORC2 Activation. J. Biol. Chem. 287 (3), 2090–2098. 10.1074/jbc.M111.323303 Feldman B. J. Feldman D. (2001). The Development of Androgen-independent Prostate Cancer. Nat. Rev. Cancer 1 (1), 34–45. 10.1038/35094009 Fernández-Pomares C. Juárez-Aguilar E. Domínguez-Ortiz M. Á. Gallegos-Estudillo J. Herrera-Covarrubias D. Sánchez-Medina A. (2018). Hydroalcoholic Extract of the Widely Used Mexican Plant Justicia Spicigera Schltdl. Exerts a Cytostatic Effect on LNCaP Prostate Cancer Cells. J. Herbal Med. 12, 66–72. 10.1016/j.hermed.2017.09.003 Flourakis M. Prevarskaya N. (2009). Insights into Ca2+ Homeostasis of Advanced Prostate Cancer Cells. Biochim. Biophys. Acta 1793 (6), 1105–1109. 10.1016/j.bbamcr.2009.01.009 Foradori C. D. Weiser M. J. Handa R. J. (2008). Non-genomic Actions of Androgens. Front. Neuroendocrinol 29 (2), 169–181. 10.1016/j.yfrne.2007.10.005 Foradori C. D. Werner S. B. Sandau U. S. Clapp T. R. Handa R. J. (2007). Activation of the Androgen Receptor Alters the Intracellular Calcium Response to Glutamate in Primary Hippocampal Neurons and Modulates Sarco/endoplasmic Reticulum Calcium ATPase 2 Transcription. Neuroscience 149 (1), 155–164. 10.1016/j.neuroscience.2007.06.054 French C. A. Miyoshi I. Kubonishi I. Grier H. E. Perez-Atayde A. R. Fletcher J. A. (2003). BRD4-NUT Fusion Oncogene: a Novel Mechanism in Aggressive Carcinoma. Cancer Res. 63 (2), 304–307. 10.1016/S0165-4608(02)00679-9 Gantar M. Dhandayuthapani S. Rathinavelu A. (2012). Phycocyanin Induces Apoptosis and Enhances the Effect of Topotecan on Prostate Cell Line LNCaP. J. Med. Food 15 (12), 1091–1095. 10.1089/jmf.2012.0123 Gapter L. Wang Z. Glinski J. Ng K. Y. (2005). Induction of Apoptosis in Prostate Cancer Cells by Pachymic Acid from Poria Cocos. Biochem. Biophys. Res. Commun. 332 (4), 1153–1161. 10.1016/j.bbrc.2005.05.044 Gille H. Kortenjann M. Thomae O. Moomaw C. Slaughter C. Cobb M. H. (1995). ERK Phosphorylation Potentiates Elk-1-mediated Ternary Complex Formation and Transactivation. EMBO J. 14 (5), 951–962. 10.1002/j.1460-2075.1995.tb07076.x Gioti K. Papachristodoulou A. Benaki D. Beloukas A. Vontzalidou A. Aligiannis N. (2020). Glycyrrhiza Glabra-Enhanced Extract and Adriamycin Antiproliferative Effect on PC-3 Prostate Cancer Cells. Nutr. Cancer 72 (2), 320–332. 10.1080/01635581.2019.1632357 Graff R. E. Ahearn T. U. Pettersson A. Ebot E. M. Gerke T. Penney K. L. (2018). Height, Obesity, and the Risk of TMPRSS2:ERG-Defined Prostate Cancer. Cancer Epidemiol. Biomarkers Prev. 27 (2), 193–200. 10.1158/1055-9965.EPI-17-0547 Grasso C. S. Wu Y. M. Robinson D. R. Cao X. Dhanasekaran S. M. Khan A. P. (2012). The Mutational Landscape of Lethal Castration-Resistant Prostate Cancer. Nature 487 (7406), 239–243. 10.1038/nature11125 Gregory K. J. Zhao B. Bielenberg D. R. Dridi S. Wu J. Jiang W. (2010). Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, Migration, and uPAR Expression of Prostate Cancer Cells. PLoS One 5 (10), e13428. 10.1371/journal.pone.0013428 Gubiani J. R. Oliveira M. C. S. Neponuceno R. A. R. Camargo M. J. Garcez W. S. Biz A. R. (2019). Cytotoxic Prenylated Indole Alkaloid Produced by the Endophytic Fungus Aspergillus terreus P63. Phytochemistry Lett. 32, 162–167. 10.1016/j.phytol.2019.06.003 Gumushan Aktas H. Akgun T. (2018). Naringenin Inhibits Prostate Cancer Metastasis by Blocking Voltage-Gated Sodium Channels. Biomed. Pharmacother. 106, 770–775. 10.1016/j.biopha.2018.07.008 Guo Z. Yang X. Sun F. Jiang R. Linn D. E. Chen H. (2009). A Novel Androgen Receptor Splice Variant Is Up-Regulated during Prostate Cancer Progression and Promotes Androgen Depletion-Resistant Growth. Cancer Res. 69 (6), 2305–2313. 10.1158/0008-5472.Can-08-3795 Gupta S. Li J. Kemeny G. Bitting R. L. Beaver J. Somarelli J. A. (2017). Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer. Clin. Cancer Res. 23 (5), 1346–1357. 10.1158/1078-0432.CCR-16-1211 Haile S. Sadar M. D. (2011). Androgen Receptor and its Splice Variants in Prostate Cancer. Cell Mol Life Sci 68 (24), 3971–3981. 10.1007/s00018-011-0766-7 Hamidullah Kumar R. Singh Saini K. Kumar A. Kumar S. Ramakrishna E. (2015). Quercetin-6-C-β-D-glucopyranoside, Natural Analog of Quercetin Exhibits Anti-prostate Cancer Activity by Inhibiting Akt-mTOR Pathway via Aryl Hydrocarbon Receptor. Biochimie 119, 68–79. 10.1016/j.biochi.2015.10.012 Han H. Qiu L. Wang X. Qiu F. Wong Y. Yao X. (2011). Physalins A and B Inhibit Androgen-independent Prostate Cancer Cell Growth through Activation of Cell Apoptosis and Downregulation of Androgen Receptor Expression. Biol. Pharm. Bull. 34(10), 1584–1588. 10.1248/bpb.34.1584 Harris E. M. Strope J. D. Beedie S. L. Huang P. A. Goey A. K. L. Cook K. M. (2018). Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models. Mar. Drugs 16 (7). 10.3390/md16070241 Hastak K. Gupta S. Ahmad N. Agarwal M. K. Agarwal M. L. Mukhtar H. (2003). Role of P53 and NF-kappaB in Epigallocatechin-3-Gallate-Induced Apoptosis of LNCaP Cells. Oncogene 22 (31), 4851–4859. 10.1038/sj.onc.1206708 He B. Lanz R. B. Fiskus W. Geng C. Yi P. Hartig S. M. (2014). GATA2 Facilitates Steroid Receptor Coactivator Recruitment to the Androgen Receptor Complex. Proc. Natl. Acad. Sci. U S A. 111 (51), 18261–18266. 10.1073/pnas.1421415111 Hellsten R. Johansson M. Dahlman A. Dizeyi N. Sterner O. Bjartell A. (2008). Galiellalactone Is a Novel Therapeutic Candidate against Hormone-Refractory Prostate Cancer Expressing Activated Stat3. Prostate 68 (3), 269–280. 10.1002/pros.20699 Ho Y. Dehm S. M. (2017). Androgen Receptor Rearrangement and Splicing Variants in Resistance to Endocrine Therapies in Prostate Cancer. Endocrinology 158 (6), 1533–1542. 10.1210/en.2017-00109 Hofland J. van Weerden W. M. Steenbergen J. Dits N. F. Jenster G. de Jong F. H. (2012). Activin A Stimulates AKR1C3 Expression and Growth in Human Prostate Cancer. Endocrinology 153 (12), 5726–5734. 10.1210/en.2011-2065 Holzapfel N. P. Holzapfel B. M. Champ S. Feldthusen J. Clements J. Hutmacher D. W. (2013). The Potential Role of Lycopene for the Prevention and Therapy of Prostate Cancer: from Molecular Mechanisms to Clinical Evidence. Int. J. Mol. Sci. 14 (7), 14620–14646. 10.3390/ijms140714620 Holzmann C. Kappel S. Kilch T. Jochum M. M. Urban S. K. Jung V. (2015). Transient Receptor Potential Melastatin 4 Channel Contributes to Migration of Androgen-Insensitive Prostate Cancer Cells. Oncotarget 6 (39), 41783–41793. 10.18632/oncotarget.6157 Hong M. Y. Seeram N. P. Heber D. (2008). Pomegranate Polyphenols Down-Regulate Expression of Androgen-Synthesizing Genes in Human Prostate Cancer Cells Overexpressing the Androgen Receptor. J. Nutr. Biochem. 19 (12), 848–855. 10.1016/j.jnutbio.2007.11.006 Horne W. C. Sanjay A. Bruzzaniti A. Baron R. (2005). The Role(s) of Src Kinase and Cbl Proteins in the Regulation of Osteoclast Differentiation and Function. Immunol. Rev. 208 (1), 106–125. 10.1111/j.0105-2896.2005.00335.x Hsieh T. Chen S. S. Wang X. Wu J. M. (1997). Regulation of Androgen Receptor (AR) and Prostate Specific Antigen (PSA) Expression in the Androgen-Responsive Human Prostate LNCaP Cells by Ethanolic Extracts of the Chinese Herbal Preparation, PC-SPES. Biochem. Mol. Biol. Int. 42 (3), 535–544. 10.1080/15216549700202941 Hsu A. Bray T. M. Helferich W. G. Doerge D. R. Ho E. (2010). Differential Effects of Whole Soy Extract and Soy Isoflavones on Apoptosis in Prostate Cancer Cells. Exp. Biol. Med. (Maywood) 235 (1), 90–97. 10.1258/ebm.2009.009128 Hsu J. C. Zhang J. Dev A. Wing A. Bjeldanes L. F. Firestone G. L. (2005). Indole-3-carbinol Inhibition of Androgen Receptor Expression and Downregulation of Androgen Responsiveness in Human Prostate Cancer Cells. Carcinogenesis 26 (11), 1896–1904. 10.1093/carcin/bgi155 Hsu J. L. Lee Y. J. Leu W. J. Dong Y. S. Pan S. L. Uang B. J. (2014). Moniliformediquinone Induces In Vitro and In Vivo Antitumor Activity through Glutathione Involved DNA Damage Response and Mitochondrial Stress in Human Hormone Refractory Prostate Cancer. J. Urol. 191 (5), 1429–1438. 10.1016/j.juro.2013.11.102 Hsu J. W. Yasmin-Karim S. King M. R. Wojciechowski J. C. Mickelsen D. Blair M. L. (2011). Suppression of Prostate Cancer Cell Rolling and Adhesion to Endothelium by 1α,25-Dihydroxyvitamin D3. Am. J. Pathol. 178 (2), 872–880. 10.1016/j.ajpath.2010.10.036 Huang C. Miller R. T. Freter C. E. (2016). Signaling Regulation and Role of Filamin A Cleavage in Ca2+-Stimulated Migration of Androgen Receptor-Deficient Prostate Cancer Cells. Oncotarget 8 (3), 3840–3853. 10.18632/oncotarget.9472 Huang D. M. Shen Y. C. Wu C. Huang Y. T. Kung F. L. Teng C. M. (2004). Investigation of Extrinsic and Intrinsic Apoptosis Pathways of New Clerodane Diterpenoids in Human Prostate Cancer PC-3 Cells. Eur. J. Pharmacol. 503 (1-3), 17–24. 10.1016/j.ejphar.2004.09.040 Huang W. J. Bi L. Y. Li Z. Z. Zhang X. Ye Y. (2013). Formononetin Induces the Mitochondrial Apoptosis Pathway in Prostate Cancer Cells via Downregulation of the IGF-1/IGF-1R Signaling Pathway. Pharm. Biol. 52 (4), 466–470. 10.3109/13880209.2013.842600 Huang Y. S. Mao J. X. Zhang L. Guo H. W. Yan C. Chen M. (2021). Antiprostate Cancer Activity of Ineupatolide Isolated from Carpesium Cernuum L. Biomed. Res. Int. 2021, 5515961. 10.1155/2021/5515961 Huang Y. W. Wang L. S. Chang H. L. Ye W. Dowd M. K. Wan P. J. (2006). Molecular Mechanisms of (-)-Gossypol-Induced Apoptosis in Human Prostate Cancer Cells. Anticancer Res. 26 (3A), 1925–1933. Huggins C. (1978). Endocrine-induced Regression of Cancers. Am. J. Surg. 136 (2), 233–238. 10.1016/0002-9610(78)90235-0 Huggins C. Hodges C. (1941). Studies in Prostate Cancer: the Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of Prostate. Janouskova H. El Tekle G. Bellini E. Udeshi N. D. Rinaldi A. Ulbricht A. (2017). Opposing Effects of Cancer-type-specific SPOP Mutants on BET Protein Degradation and Sensitivity to BET Inhibitors. Nat. Med. 23 (9), 1046–1054. 10.1038/nm.4372 Jeon Y. J. Jung S. N. Chang H. Yun J. Lee C. W. Lee J. (2015a). Artocarpus Altilis (Parkinson) Fosberg Extracts and Geranyl Dihydrochalcone Inhibit STAT3 Activity in Prostate Cancer DU145 Cells. Phytother Res. 29 (5), 749–756. 10.1002/ptr.5311 Jeon Y. J. Jung S. N. Yun J. Lee C. W. Choi J. Lee Y. J. (2015b). Ginkgetin Inhibits the Growth of DU-145 Prostate Cancer Cells through Inhibition of Signal Transducer and Activator of Transcription 3 Activity. Cancer Sci. 106 (4), 413–420. 10.1111/cas.12608 Jia S. Gao X. Lee S. H. Maira S. M. Wu X. Stack E. C. (2013). Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention. Cancer Discov. 3 (1), 44–51. 10.1158/2159-8290.CD-12-0262 Jiang H. Sun J. Xu Q. Liu Y. Wei J. Young C. Y. (2013). Marchantin M: a Novel Inhibitor of Proteasome Induces Autophagic Cell Death in Prostate Cancer Cells. Cell Death Dis 4 (8), e761. 10.1038/cddis.2013.285 Jiang J. Eliaz I. Sliva D. (2011). Suppression of Growth and Invasive Behavior of Human Prostate Cancer Cells by ProstaCaidâ„¢: Mechanism of Activity. Int. J. Oncol. 38 (6), 1675–1682. 10.3892/ijo.2011.996 Jiang S. Zu Y. Fu Y. Zhang Y. Efferth T. (2008). Activation of the Mitochondria-Driven Pathway of Apoptosis in Human PC-3 Prostate Cancer Cells by a Novel Hydrophilic Paclitaxel Derivative, 7-Xylosyl-10-Deacetylpaclitaxel. Int. J. Oncol. 33 (1), 103–111. 10.3892/ijo.33.1.103 Jin Y. Kim Y. H. Park J. Y. Lee Y. J. Oh H. M. Choi S. K. (2018). Methyllucidone Inhibits STAT3 Activity by Regulating the Expression of the Protein Tyrosine Phosphatase MEG2 in DU145 Prostate Carcinoma Cells. Bioorg. Med. Chem. Lett. 28 (5), 853–857. 10.1016/j.bmcl.2018.02.012 Jongsomchai K. Leardkamolkarn V. Mahatheeranont S. (2020). A rice Bran Phytochemical, Cyanidin 3-glucoside, Inhibits the Progression of PC3 Prostate Cancer Cell. Anat. Cel Biol 53 (4), 481–492. 10.5115/acb.20.085 Jung S. N. Shin D. S. Kim H. N. Jeon Y. J. Yun J. Lee Y. J. (2015). Sugiol Inhibits STAT3 Activity via Regulation of Transketolase and ROS-Mediated ERK Activation in DU145 Prostate Carcinoma Cells. Biochem. Pharmacol. 97 (1), 38–50. 10.1016/j.bcp.2015.06.033 Kandoth C. (2013). Cancer Genome Atlas Research Network. Nature 497 (7447), 67–73. Kasimsetty S. G. Bialonska D. Reddy M. K. Thornton C. Willett K. L. Ferreira D. (2009). Effects of Pomegranate Chemical Constituents/intestinal Microbial Metabolites on CYP1B1 in 22Rv1 Prostate Cancer Cells. J. Agric. Food Chem. 57 (22), 10636–10644. 10.1021/jf902716r Kaur M. Velmurugan B. Rajamanickam S. Agarwal R. Agarwal C. (2009). Gallic Acid, an Active Constituent of Grape Seed Extract, Exhibits Anti-proliferative, Pro-apoptotic and Anti-tumorigenic Effects against Prostate Carcinoma Xenograft Growth in Nude Mice. Pharm. Res. 26 (9), 2133–2140. 10.1007/s11095-009-9926-y Khan F. Pandey P. Ahmad V. Upadhyay T. K. (2020a). Moringa Oleifera Methanolic Leaves Extract Induces Apoptosis and G0/G1 Cell Cycle Arrest via Downregulation of Hedgehog Signaling Pathway in Human Prostate PC-3 Cancer Cells. J. Food Biochem. 44 (8), e13338. 10.1111/jfbc.13338 Khan F. Pandey P. Jha N. K. Jafri A. Khan I. (2020b). Antiproliferative Effect of Moringa Oleifera Methanolic Leaf Extract by Down-Regulation of Notch Signaling in DU145 Prostate Cancer Cells. Gene Rep. 19, 100619. 10.1016/j.genrep.2020.100619 Khan N. Asim M. Afaq F. Abu Zaid M. Mukhtar H. (2008). A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice. Cancer Res. 68 (20), 8555–8563. 10.1158/0008-5472.CAN-08-0240 Kilch T. Kappel S. Peinelt C. (2016). Regulation of Ca(2+) Signaling in Prostate Cancer Cells. Channels (Austin) 10 (4), 170–171. 10.1080/19336950.2015.1137176 Kim K. Y. Cho H. J. Yu S. N. Kim S. H. Yu H. S. Park Y. M. (2013). Interplay of Reactive Oxygen Species, Intracellular Ca2+ and Mitochondrial Homeostasis in the Apoptosis of Prostate Cancer Cells by Deoxypodophyllotoxin. J. Cel Biochem 114 (5), 1124–1134. 10.1002/jcb.24455 Kim S. H. Bommareddy A. Singh S. V. (2011). Garlic Constituent Diallyl Trisulfide Suppresses X-Linked Inhibitor of Apoptosis Protein in Prostate Cancer Cells in Culture and In Vivo . Cancer Prev. Res. (Phila) 4 (6), 897–906. 10.1158/1940-6207.CAPR-10-0323 Kimira M. Arai Y. Shimoi K. Watanabe S. (1998). Japanese Intake of Flavonoids and Isoflavonoids from Foods. J. Epidemiol. 8 (3), 168–175. 10.2188/jea.8.168 Koka P. S. Mondal D. Schultz M. Abdel-Mageed A. B. Agrawal K. C. (2010). Studies on Molecular Mechanisms of Growth Inhibitory Effects of Thymoquinone against Prostate Cancer Cells: Role of Reactive Oxygen Species. Exp. Biol. Med. (Maywood) 235 (6), 751–760. 10.1258/ebm.2010.009369 Kong E. H. Kim Y. J. Kim Y. J. Cho H. J. Yu S. N. Kim K. Y. (2008). Piplartine Induces Caspase-Mediated Apoptosis in PC-3 Human Prostate Cancer Cells. Oncol. Rep. 20 (4), 785–792. 10.3892/or_00000075 Koyama S. Cobb L. J. Mehta H. H. Seeram N. P. Heber D. Pantuck A. J. (2010). Pomegranate Extract Induces Apoptosis in Human Prostate Cancer Cells by Modulation of the IGF-IGFBP axis. Growth Horm. IGF Res. 20 (1), 55–62. 10.1016/j.ghir.2009.09.003 Kron K. J. Murison A. Zhou S. Huang V. Yamaguchi T. N. Shiah Y. J. (2017). TMPRSS2-ERG Fusion Co-opts Master Transcription Factors and Activates NOTCH Signaling in Primary Prostate Cancer. Nat. Genet. 49 (9), 1336–1345. 10.1038/ng.3930 Kumar A. Coleman I. Morrissey C. Zhang X. True L. D. Gulati R. (2016). Substantial Interindividual and Limited Intraindividual Genomic Diversity Among Tumors from Men with Metastatic Prostate Cancer. Nat. Med. 22 (4), 369–378. 10.1038/nm.4053 Labow R. S. Layne D. S. (1972). The Formation of Glucosides of Isoflavones and of Some Other Phenols by Rabbit Liver Microsomal Fractions. Biochem. J. 128 (3), 491–497. 10.1042/bj1280491 Lee D. H. Szczepanski M. J. Lee Y. J. (2009). Magnolol Induces Apoptosis via Inhibiting the EGFR/PI3K/Akt Signaling Pathway in Human Prostate Cancer Cells. J. Cel Biochem 106 (6), 1113–1122. 10.1002/jcb.22098 Lee E. Son J. E. Byun S. Lee S. J. Kim Y. A. Liu K. (2013a). CDK2 and mTOR Are Direct Molecular Targets of Isoangustone A in the Suppression of Human Prostate Cancer Cell Growth. Toxicol. Appl. Pharmacol. 272 (1), 12–20. 10.1016/j.taap.2013.04.030 Lee M. G. Liu Y. C. Lee Y. L. El-Shazly M. Lai K. H. Shih S. P. (2018). Heteronemin, a Marine Sesterterpenoid-type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90. Mar. Drugs 16 (6). 10.3390/md16060204 Lee S.-E. Sivtseva S. Lim C. Okhlopkova Z. Cho S. (2021). Artemisia Kruhsiana Leaf Extract Induces Autophagic Cell Death in Human Prostate Cancer Cells. Chin. J. Nat. Medicines 19 (2), 134–142. 10.1016/s1875-5364(21)60014-6 Lee S. E. Okhlopkova Z. Lim C. Cho S. (2020). Dracocephalum Palmatum Stephan Extract Induces Apoptosis in Human Prostate Cancer Cells via the Caspase-8-Mediated Extrinsic Pathway. Chin. J. Nat. Med. 18 (10), 793–800. 10.1016/s1875-5364(20)60019-x Lee S. Y. Cho J. S. Yuk D. Y. Moon D. C. Jung J. K. Yoo H. S. (2009). Obovatol Enhances Docetaxel-Induced Prostate and Colon Cancer Cell Death through Inactivation of Nuclear Transcription Factor-Κb. J. Pharmacol. Sci. 111 (2), 124–136. 10.1254/jphs.09048fp Lee W. Kim K. Y. Yu S. N. Kim S. H. Chun S. S. Ji J. H. (2013b). Pipernonaline from Piper Longum Linn. Induces ROS-Mediated Apoptosis in Human Prostate Cancer PC-3 Cells. Biochem. Biophys. Res. Commun. 430 (1), 406–412. 10.1016/j.bbrc.2012.11.030 Leu W. J. Chang H. S. Chan S. H. Hsu J. L. Yu C. C. Hsu L. C. (2014). Reevesioside A, a Cardenolide Glycoside, Induces Anticancer Activity against Human Hormone-Refractory Prostate Cancers through Suppression of C-Myc Expression and Induction of G1 Arrest of the Cell Cycle. Plos One 9 (1), e87323. 10.1371/journal.pone.0087323 Levrier C. Sadowski M. C. Rockstroh A. Gabrielli B. Kavallaris M. Lehman M. (2016). 6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells. Mol. Cancer Ther. 16 (1), 3–15. 10.1158/1535-7163.mct-16-0325 Lewandowska U. Szewczyk K. Owczarek K. Hrabec Z. Podsędek A. Koziołkiewicz M. (2013). Flavanols from Japanese Quince (Chaenomeles Japonica) Fruit Inhibit Human Prostate and Breast Cancer Cell Line Invasiveness and Cause Favorable Changes in Bax/Bcl-2 mRNA Ratio. Nutr. Cancer 65 (2), 273–285. 10.1080/01635581.2013.749292 Li C. Han X. Zhang H. Wu J. Li B. (2015a). Effect of Scopoletin on Apoptosis and Cell Cycle Arrest in Human Prostate Cancer Cells In Vitro . Trop. J. Pharm. Res. 14 (4), 611–617. 10.4314/tjpr.v14i4.8 Li C. He C. Xu Y. Xu H. Tang Y. Chavan H. (2019). Alternol Eliminates Excessive ATP Production by Disturbing Krebs Cycle in Prostate Cancer. Prostate 79, 628–639. 10.1002/pros.23767 Li J. Al-Azzawi F. (2009). Mechanism of Androgen Receptor Action. Maturitas 63 (2), 142–148. 10.1016/j.maturitas.2009.03.008 Li Q. Q. Wang G. Huang F. Banda M. Reed E. (2010). Antineoplastic Effect of Beta-Elemene on Prostate Cancer Cells and Other Types of Solid Tumour Cells. J. Pharm. Pharmacol. 62 (8), 1018–1027. 10.1111/j.2042-7158.2010.01135.x Li T. Zhao X. Mo Z. Huang W. Yan H. Ling Z. (2014). Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells. Cell Physiol Biochem 34 (4), 1351–1358. 10.1159/000366342 Li W. (2020). Isolobetyol, a New Polyacetylene Derivative from Platycodon Grandiflorum Root. Nat. Prod. Res., 1–4. 10.1080/14786419.2020.1779269 Li W. Li D.-Y. Wang H.-D. Zheng Z.-J. Hu J. Li Z.-Z. (2015b). Juglans Regia Hexane Extract Exerts Antitumor Effect, Apoptosis Induction and Cell Circle Arrest in Prostate Cancer Cells In Vitro . Trop. J. Pharm. Res. 14 (3), 399. 10.4314/tjpr.v14i3.7 Li X. Fan S. Pan X. Xiaokaiti Y. Duan J. Shi Y. (2016). Nordihydroguaiaretic Acid Impairs Prostate Cancer Cell Migration and Tumor Metastasis by Suppressing Neuropilin 1. Oncotarget 7 (52), 86225–86238. 10.18632/oncotarget.13368 Li X. Lao Y. Zhang H. Wang X. Tan H. Lin Z. (2015c). The Natural Compound Guttiferone F Sensitizes Prostate Cancer to Starvation Induced Apoptosis via Calcium and JNK Elevation. BMC Cancer 15 (1), 254. 10.1186/s12885-015-1292-z Li X. Li X. Wang J. Ye Z. Li J. C. (2012). Oridonin Up-Regulates Expression of P21 and Induces Autophagy and Apoptosis in Human Prostate Cancer Cells. Int. J. Biol. Sci. 8 (6), 901–912. 10.7150/ijbs.4554 Li Y. Chan S. C. Brand L. J. Hwang T. H. Silverstein K. A. Dehm S. M. (2013). Androgen Receptor Splice Variants Mediate Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cell Lines. Cancer Res. 73 (2), 483–489. 10.1158/0008-5472.CAN-12-3630 Li Y. Sarkar F. H. (2002). Inhibition of Nuclear Factor kappaB Activation in PC3 Cells by Genistein Is Mediated via Akt Signaling Pathway. Clin. Cancer Res. 8 (7), 2369–2377. 10.1159/000064924 Liao R. S. Ma S. Miao L. Li R. Yin Y. Raj G. V. (2013). Androgen Receptor-Mediated Non-genomic Regulation of Prostate Cancer Cell Proliferation. Transl Androl. Urol. 2 (3), 187–196. 10.3978/j.issn.2223-4683.2013.09.07 Liberio M. S. Sadowski M. C. Davis R. A. Rockstroh A. Vasireddy R. Lehman M. L. (2015). The Ascidian Natural Product Eusynstyelamide B Is a Novel Topoisomerase II Poison that Induces DNA Damage and Growth Arrest in Prostate and Breast Cancer Cells. Oncotarget 6 (41), 43944–43963. 10.18632/oncotarget.6267 Lin C. C. Chen K. B. Tsai C. H. Tsai F. J. Huang C. Y. Tang C. H. (2019). Casticin Inhibits Human Prostate Cancer DU 145 Cell Migration and Invasion via Ras/Akt/NF‐κB Signaling Pathways. J. Food Biochem. 43. 10.1111/jfbc.12902 Lippert M. C. Mcclain R. Boyd J. C. Theodorescu D. (1999). Alternative Medicine Use in Patients with Localized Prostate Carcinoma Treated with Curative Intent. Cancer 86 (12), 2642–2648. 10.1002/(SICI)1097-0142(19991215)86:123.0.CO;2-4 Liu K. Park C. Li S. Lee K. W. Liu H. He L. (2012a). Aloe-emodin Suppresses Prostate Cancer by Targeting the mTOR Complex 2. Carcinogenesis 33 (7), 1406–1411. 10.1093/carcin/bgs156 Liu P. Cheng H. Roberts T. M. Zhao J. J. (2009). Targeting the Phosphoinositide 3-kinase Pathway in Cancer. Nat. Rev. Drug Discov. 8 (8), 627–644. 10.1038/nrd2926 Liu S. Kumari S. Hu Q. Senapati D. Venkadakrishnan V. B. Wang D. (2017). A Comprehensive Analysis of Coregulator Recruitment, Androgen Receptor Function and Gene Expression in Prostate Cancer. Elife 6, e28482. 10.7554/eLife.28482 Liu W. K. Cheung F. W. Che C. T. (2006). Stellettin A Induces Oxidative Stress and Apoptosis in HL-60 Human Leukemia and LNCaP Prostate Cancer Cell Lines. J. Nat. Prod. 69 (6), 934–937. 10.1021/np058122y Liu X. He Z. Li C. H. Huang G. Ding C. Liu H. (2012b). Correlation Analysis of JAK-STAT Pathway Components on Prognosis of Patients with Prostate Cancer. Pathol. Oncol. Res. 18 (1), 17–23. 10.1007/s12253-011-9410-y Liu Y. Wang M. Wang D. Li X. Wang W. Lou H. (2016). Malformin A1 Promotes Cell Death through Induction of Apoptosis, Necrosis and Autophagy in Prostate Cancer Cells. Cancer Chemother. Pharmacol. 77 (1), 63–75. 10.1007/s00280-015-2915-4 Locke J. A. Guns E. S. Lubik A. A. Adomat H. H. Hendy S. C. Wood C. A. (2008). Androgen Levels Increase by Intratumoral De Novo Steroidogenesis during Progression of Castration-Resistant Prostate Cancer. Cancer Res. 68 (15), 6407–6415. 10.1158/0008-5472.CAN-07-5997 Lu Z. Wang H. Zhu M. Song W. Wang J. Wu C. (2018). Ophiopogonin D', a Natural Product from Radix Ophiopogonis, Induces In Vitro and In Vivo RIPK1-dependent and Caspase-independent Apoptotic Death in Androgen-independent Human Prostate Cancer Cells. Front. Pharmacol. 9, 432. 10.3389/fphar.2018.00432 Luu-The V. Bélanger A. Labrie F. (2008). Androgen Biosynthetic Pathways in the Human Prostate. Best Pract. Res. Clin. Endocrinol. Metab. 22 (2), 207–221. 10.1016/j.beem.2008.01.008 Ma B. Zhang H. Wang Y. Zhao A. Zhu Z. Bao X. (2018). Corosolic Acid, a Natural Triterpenoid, Induces ER Stress-dependent Apoptosis in Human Castration Resistant Prostate Cancer Cells via Activation of IRE-1/JNK, PERK/CHOP and TRIB3. J. Exp. Clin. Cancer Res. 37 (1), 210. 10.1186/s13046-018-0889-x Malik A. Afaq F. Sarfaraz S. Adhami V. M. Syed D. N. Mukhtar H. (2005). Pomegranate Fruit Juice for Chemoprevention and Chemotherapy of Prostate Cancer. Proc. Natl. Acad. Sci. U S A. 102 (41), 14813–14818. 10.1073/pnas.0505870102 Marais R. Wynne J. Treisman R. (1993). The SRF Accessory Protein Elk-1 Contains a Growth Factor-Regulated Transcriptional Activation Domain. Cell 73 (2), 381–393. 10.1016/0092-8674(93)90237-k Marilena M. Sims N. A. Susanne V. Silvia M. Anna T. Silvia B. (2000). Decreased C-Src Expression Enhances Osteoblast Differentiation and Bone Formation. J. Cel Biol. 151 (2), 311–320. Masood M. Rasul A. Sarfraz I. Jabeen F. Liu S. Liu X. (2019).Hispolon Induces Apoptosis against Prostate DU145 Cancer Cells via Modulation of Mitochondrial and STAT3 Pathways Pak J. Pharm. Sci., 32, 2237–2243. Masoodi K. Z. Wani W. Dar Z. A. Mansoor S. Anam-ul-Haq S. Farooq I. (2020). Sea Buckthorn (Hippophae Rhamnoides L.) Inhibits Cellular Proliferation, Wound Healing and Decreases Expression of Prostate Specific Antigen in Prostate Cancer Cells In Vitro . J. Funct. Foods 73, 104102. 10.1016/j.jff.2020.104102 McEleny K. R. Watson R. W. Coffey R. N. O'Neill A. J. Fitzpatrick J. M. (2002). Inhibitors of Apoptosis Proteins in Prostate Cancer Cell Lines. Prostate 51 (2), 133–140. 10.1002/pros.10061 Meimetis L. G. Williams D. E. Mawji N. R. Banuelos C. A. Lal A. A. Park J. J. (2012). Niphatenones, Glycerol Ethers from the Sponge Niphates Digitalis Block Androgen Receptor Transcriptional Activity in Prostate Cancer Cells: Structure Elucidation, Synthesis, and Biological Activity. J. Med. Chem. 55 (1), 503–514. 10.1021/jm2014056 Meng F. M. Yang J. B. Yang C. H. Jiang Y. Zhou Y. F. Yu B. (2012). Vitexicarpin Induces Apoptosis in Human Prostate Carcinoma PC-3 Cells through G2/M Phase Arrest. Asian Pac. J. Cancer Prev. 13 (12), 6369–6374. 10.7314/Apjcp.2012.13.12.6369 Meng Y. Lin Z. M. Ge N. Zhang D. L. Huang J. Kong F. (2015). Ursolic Acid Induces Apoptosis of Prostate Cancer Cells via the PI3K/Akt/mTOR Pathway. Am. J. Chin. Med. 43 (7), 1471–1486. 10.1142/S0192415X15500834 Miao L. Yun X. Tao R. Wang Y. Fan G. Zhu Y. (2018). Bakuchiol Exhibits Anti-metastasis Activity through NF-Κb Cross-Talk Signaling with AR and ERβ in Androgen-independent Prostate Cancer Cells PC-3. J. Pharmacol. Sci. 138, 1–8. 10.1016/j.jphs.2017.04.004 Migliaccio A. Castoria G. Di Domenico M. de Falco A. Bilancio A. Lombardi M. (2002). Sex Steroid Hormones Act as Growth Factors. J. Steroid Biochem. Mol. Biol. 83 (1), 31–35. 10.1016/s0960-0760(02)00264-9 Miller W. L. Auchus R. J. (2011). The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and its Disorders. Endocr. Rev. 32 (1), 81–151. 10.1210/er.2010-0013 Ming M. Sun F. Y. Zhang W. T. Liu J. K. (2016). Therapeutic Effect of Oridonin on Mice with Prostate Cancer. Asian Pac. J. Trop. Med. 9 (2), 184–187. 10.1016/j.apjtm.2016.01.007 Mirza M. B. Elkady A. I. Al-Attar A. M. Syed F. Q. Mohammed F. A. Hakeem K. R. (2018). Induction of Apoptosis and Cell Cycle Arrest by Ethyl Acetate Fraction of Phoenix Dactylifera L. (Ajwa Dates) in Prostate Cancer Cells. J. Ethnopharmacol 218, 35–44. 10.1016/j.jep.2018.02.030 Montgomery R. B. Mostaghel E. A. Vessella R. Hess D. L. Kalhorn T. F. Higano C. S. (2008). Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: a Mechanism for Castration-Resistant Tumor Growth. Cancer Res. 68 (11), 4447–4454. 10.1158/0008-5472.CAN-08-0249 Mordan-McCombs S. Brown T. Wang W. L. Gaupel A. C. Welsh J. Tenniswood M. (2010). Tumor Progression in the LPB-Tag Transgenic Model of Prostate Cancer Is Altered by Vitamin D Receptor and Serum Testosterone Status. J. Steroid Biochem. Mol. Biol. 121 (2), 368–371. 10.1016/j.jsbmb.2010.03.062 Morgentaler A. (2009). Testosterone Therapy in Men with Prostate Cancer: Scientific and Ethical Considerations. J. Urol. 181 (3), 972–979. 10.1016/j.juro.2008.11.031 Mukhtar E. Adhami V. M. Sechi M. Mukhtar H. (2015). Dietary Flavonoid Fisetin Binds to β-tubulin and Disrupts Microtubule Dynamics in Prostate Cancer Cells. Cancer Lett. 367 (2), 173–183. 10.1016/j.canlet.2015.07.030 Mundy G. R. (2002). Metastasis to Bone: Causes, Consequences and Therapeutic Opportunities. Nat. Rev. Cancer 2 (8), 584–593. 10.1038/nrc867 Nakase I. Gallis B. Takatani-Nakase T. Oh S. Lacoste E. Singh N. P. (2009). Transferrin Receptor-dependent Cytotoxicity of Artemisinin-Transferrin Conjugates on Prostate Cancer Cells and Induction of Apoptosis. Cancer Lett. 274 (2), 290–298. 10.1016/j.canlet.2008.09.023 Nam R. K. Fleshner N. Rakovitch E. Klotz L. Trachtenberg J. Choo R. (1999). Prevalence and Patterns of the Use of Complementary Therapies Among Prostate Cancer Patients: an Epidemiological Analysis. J. Urol. 161 (5), 1521–1524. 10.1108/1359854091097007210.1097/00005392-199905000-00028 Network C. G. A. (2015a). The Molecular Taxonomy of Primary Prostate Cancer. Cell 163 (4), 1011–1025. 10.1016/j.cell.2015.10.025 Network T. C. G. A. (2015b). The Molecular Taxonomy of Primary Prostate Cancer. Cell 163 (4), 1011–1025. 10.1016/j.cell.2015.10.025 Nguyen C. Mehaidli A. Baskaran K. Grewal S. Pupulin A. Ruvinov I. (2019). Dandelion Root and Lemongrass Extracts Induce Apoptosis, Enhance Chemotherapeutic Efficacy, and Reduce Tumour Xenograft Growth In Vivo in Prostate Cancer. Evid. Based Complement. Alternat Med. 2019, 2951428. 10.1155/2019/2951428 Nishimura M. Fuchino H. Takayanagi K. Kawakami H. Nakayama H. Kawahara N. (2021). Toxicity of Jegosaponins A and B from Styrax japonica Siebold Zuccarini in Prostate Cancer Cells and Zebrafish Embryos Resulting from Increased Membrane Permeability. Ijms 22 (12), 6354. 10.3390/ijms22126354 Pan X. Y. Guo H. Han J. Hao F. An Y. Xu Y. (2012). Ginsenoside Rg3 Attenuates Cell Migration via Inhibition of Aquaporin 1 Expression in PC-3M Prostate Cancer Cells. Eur. J. Pharmacol. 683 (1–3), 27–34. 10.1016/j.ejphar.2012.02.040 Pintard L. Willis J. H. Willems A. Johnson J. L. Srayko M. Kurz T. (2003). The BTB Protein MEL-26 Is a Substrate-specific Adaptor of the CUL-3 Ubiquitin-Ligase. Nature 425 (6955), 311–316. 10.1038/nature01959 Pinto J. T. Sinha R. Papp K. Facompre N. D. Desai D. El-Bayoumy K. (2007). Differential Effects of Naturally Occurring and Synthetic Organoselenium Compounds on Biomarkers in Androgen Responsive and Androgen Independent Human Prostate Carcinoma Cells. Int. J. Cancer 120 (7), 1410–1417. 10.1002/ijc.22500 Pradhan N. Parbin S. Kausar C. Kar S. Mawatwal S. Das L. (2019). Paederia Foetida Induces Anticancer Activity by Modulating Chromatin Modification Enzymes and Altering Pro-inflammatory Cytokine Gene Expression in Human Prostate Cancer Cells. Food Chem. Toxicol. 130, 161–173. 10.1016/j.fct.2019.05.016 Rabiau N. Kossaï M. Braud M. Chalabi N. Satih S. Bignon Y. J. (2010). Genistein and Daidzein Act on a Panel of Genes Implicated in Cell Cycle and Angiogenesis by Polymerase Chain Reaction Arrays in Human Prostate Cancer Cell Lines. Cancer Epidemiol. 34 (2), 200–206. 10.1016/j.canep.2009.12.018 Ritch C. R. Cookson M. S. (2016). Advances in the Management of Castration Resistant Prostate Cancer. BMJ 355, i4405. 10.1136/bmj.i4405 Robinson D. Van Allen E. M. Wu Y. M. Schultz N. Lonigro R. J. Mosquera J. M. (2015). Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 161 (5), 1215–1228. 10.1016/j.cell.2015.05.001 Rodrigues D. N. Boysen G. Sumanasuriya S. Seed G. Marzo A. M. de Bono J. (2017). The Molecular Underpinnings of Prostate Cancer: Impacts on Management and Pathology Practice. J. Pathol. 241 (2), 173–182. 10.1002/path.4826 Rodríguez-Berriguete G. Torrealba N. Fraile B. Paniagua R. Royuela M. (2016). Epidermal Growth Factor Induces P38 MAPK-dependent G0/G1-To-S Transition in Prostate Cancer Cells upon Androgen Deprivation Conditions. Growth Factors 34 (1-2), 5–10. 10.3109/08977194.2015.1132712 Rosa H. H. Carvalho P. Ortmann C. F. Schneider N. F. Z. Reginatto F. H. Simões C. M. O. (2020). Cytotoxic Effects of a Triterpene-Enriched Fraction of Cecropia Pachystachya on the Human Hormone-Refractory Prostate Cancer PC3 Cell Line. Biomed. Pharmacother. 130, 110551. 10.1016/j.biopha.2020.110551 Russo A. Piovano M. Clericuzio M. Lombardo L. Tabasso S. Chamy M. C. (2007). Putrescine-1,4-dicinnamide from Pholiota Spumosa (Basidiomycetes) Inhibits Cell Growth of Human Prostate Cancer Cells. Phytomedicine 14 (2-3), 185–191. 10.1016/j.phymed.2006.09.010 Ryan C. J. Tindall D. J. (2011). Androgen Receptor Rediscovered: the New Biology and Targeting the Androgen Receptor Therapeutically. J. Clin. Oncol. 29 (27), 3651–3658. 10.1200/JCO.2011.35.2005 Sachan R. Kundu A. Jeon Y. Choi W. S. Yoon K. Kim I. S. (2018). Afrocyclamin A, a Triterpene Saponin, Induces Apoptosis and Autophagic Cell Death via the PI3K/Akt/mTOR Pathway in Human Prostate Cancer Cells. Phytomedicine 51, 139–150. 10.1016/j.phymed.2018.10.012 Sajjadi S.-E. Ghanadian M. Aghaei M. Salehi A. (2018). Two New Dammarane Triterpenes Isolated from Cleome Khorassanica Bunge & Bien with Cytotoxicity against DU-145 and LNCaP Prostate Cancer Cell Lines. J. Asian Nat. Prod. Res. 22, 38–46. 10.1080/10286020.2018.1538211 Salmani J. M. M. Zhang X. P. Jacob J. A. Chen B. A. (2017). Apigenin's Anticancer Properties and Molecular Mechanisms of Action: Recent Advances and Future Prospectives. Chin. J. Nat. Med. 15 (5), 321–329. 10.1016/S1875-5364(17)30052-3 Saravanakumar K. Mandava S. Chellia R. Jeevithan E. Babu Yelamanchi R. S. Mandava D. (2019). Novel Metabolites from Trichoderma Atroviride against Human Prostate Cancer Cells and Their Inhibitory Effect on Helicobacter pylori and Shigella Toxin Producing Escherichia coli . Microb. Pathogenesis 126, 19–26. 10.1016/j.micpath.2018.10.011 Sarveswaran S. Gautam S. C. Ghosh J. (2012). Wedelolactone, a Medicinal Plant-Derived Coumestan, Induces Caspase-dependent Apoptosis in Prostate Cancer Cells via Downregulation of PKCε without Inhibiting Akt. Int. J. Oncol. 41 (6), 2191–2199. 10.3892/ijo.2012.1664 Sarveswaran S. Liroff J. Zhou Z. Nikitin A. Y. Ghosh J. (2010). Selenite Triggers Rapid Transcriptional Activation of P53, and P53-Mediated Apoptosis in Prostate Cancer Cells: Implication for the Treatment of Early-Stage Prostate Cancer. Int. J. Oncol. 36 (6), 1419–1428. 10.3892/ijo_00000627 Scher H. I. Sawyers C. L. (2005). Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling axis. J. Clin. Oncol. 23 (32), 8253–8261. 10.1200/JCO.2005.03.4777 Schindler C. Darnell J. E. (1995). Transcriptional Responses to Polypeptide Ligands: the JAK-STAT Pathway. Annu. Rev. Biochem. 64 (64), 621–651. 10.1146/annurev.bi.64.070195.003201 Schleich S. Papaioannou M. Baniahmad A. Matusch R. (2006). Activity-guided Isolation of an Antiandrogenic Compound of Pygeum Africanum. Planta Med. 72 (6), 547–551. 10.1055/s-2006-941472 Schweizer M. T. Plymate S. R. (2016). Targeting Constitutively Active Androgen Receptor Splice Variants in Castration Resistant Prostate Cancer. Expert Opin. Ther. Targets 20 (8), 903–906. 10.1517/14728222.2016.1159676 Senderowicz A. M. Kaur G. Sainz E. Laing C. Inman W. D. Rodríguez J. (1995). Jasplakinolide's Inhibition of the Growth of Prostate Carcinoma Cells In Vitro with Disruption of the Actin Cytoskeleton. J. Natl. Cancer Inst. 87 (1), 46–51. 10.1093/jnci/87.1.46 Seo Y. Ryu K. Park J. Jeon D. K. Jo S. Lee H. K. (2017). Inhibition of ANO1 by Luteolin and its Cytotoxicity in Human Prostate Cancer PC-3 Cells. PLoS One 12 (3), e0174935. 10.1371/journal.pone.0174935 Shanmugam M. K. Rajendran P. Li F. Nema T. Vali S. Abbasi T. (2011). Ursolic Acid Inhibits Multiple Cell Survival Pathways Leading to Suppression of Growth of Prostate Cancer Xenograft in Nude Mice. J. Mol. Med. (Berl) 89 (7), 713–727. 10.1007/s00109-011-0746-2 Shaw G. Renfree M. B. Leihy M. W. Shackleton C. H. L. Roitman E. Wilson J. D. (2000). Prostate Formation in a Marsupial Is Mediated by the Testicular Androgen 5alpha -androstane-3alpha ,17beta -diol. Proc. Natl. Acad. Sci. 97 (22), 12256–12259. 10.1073/pnas.220412297 Sheng Y. Zou M. Wang Y. Li Q. (2015). 2',4'-dihydroxychalcone, a Flavonoid Isolated from Herba Oxytropis, Suppresses PC-3 Human Prostate Cancer Cell Growth by Induction of Apoptosis. Oncol. Lett. 10 (6), 3737–3741. 10.3892/ol.2015.3795 Shigemura K. Arbiser J. L. Sun S. Y. Zayzafoon M. Johnstone P. A. Fujisawa M. (2007). Honokiol, a Natural Plant Product, Inhibits the Bone Metastatic Growth of Human Prostate Cancer Cells. Cancer 109 (7), 1279–1289. 10.1002/cncr.22551 Shin Y. Kim G. D. Jeon J. E. Shin J. Lee S. K. (2013). Antimetastatic Effect of Halichondramide, a Trisoxazole Macrolide from the marine Sponge Chondrosia Corticata, on Human Prostate Cancer Cells via Modulation of Epithelial-To-Mesenchymal Transition. Mar. Drugs 11 (7), 2472–2485. 10.3390/md11072472 Siegel R. L. Miller K. D. Fedewa S. A. Ahnen D. J. Meester R. G. S. Barzi A. (2017). Colorectal Cancer Statistics, 2017. CA Cancer J. Clin. 67 (3), 177–193. 10.3322/caac.21395 Sigstedt S. C. Hooten C. J. Callewaert M. C. Jenkins A. R. Romero A. E. Pullin M. J. (2008). Evaluation of Aqueous Extracts of Taraxacum officinale on Growth and Invasion of Breast and Prostate Cancer Cells. Int. J. Oncol. 32 (5), 1085–1090. 10.3892/ijo.32.5.1085 Singh S. V. Zeng Y. Xiao D. Vogel V. G. Nelson J. B. Dhir R. (2005). Caspase-dependent Apoptosis Induction by Guggulsterone, a Constituent of Ayurvedic Medicinal Plant Commiphora Mukul, in PC-3 Human Prostate Cancer Cells Is Mediated by Bax and Bak. Mol. Cancer Ther. 4 (11), 1747–1754. 10.1158/1535-7163.MCT-05-0223 Small E. J. Halabi S. Dawson N. A. Stadler W. M. Rini B. I. Picus J. (2004). Antiandrogen Withdrawal Alone or in Combination with Ketoconazole in Androgen-independent Prostate Cancer Patients: a Phase III Trial (CALGB 9583). J. Clin. Oncol. 22 (6), 1025–1033. 10.1200/JCO.2004.06.037 Squire J. A. Park P. C. Yoshimoto M. Alami J. Williams J. L. Evans A. (2011). Prostate Cancer as a Model System for Genetic Diversity in Tumors. Adv. Cancer Res. 112, 183–216. 10.1016/B978-0-12-387688-1.00007-7 Steigerová J. Rárová L. Oklešt'ková J. Křížová K. Levková M. Sváchová M. (2012). Mechanisms of Natural Brassinosteroid-Induced Apoptosis of Prostate Cancer Cells. Food Chem. Toxicol. 50 (11), 4068–4076. 10.1016/j.fct.2012.08.031 Stein M. N. Goodin S. Dipaola R. S. (2012). Abiraterone in Prostate Cancer: a New Angle to an Old Problem. Clin. Cancer Res. 18 (7), 1848–1854. 10.1158/1078-0432.CCR-11-1805 Su X. Li T. Liu Z. Huang Q. Liao K. Ren R. (2018). Licochalcone A Activates Keap1-Nrf2 Signaling to Suppress Arthritis via Phosphorylation of P62 at Serine 349. Free Radic. Biol. Med. 115, 471–483. 10.1016/j.freeradbiomed.2017.12.004 Su Z. Y. Khor T. O. Shu L. Lee J. H. Saw C. L. Wu T. Y. (2013). Epigenetic Reactivation of Nrf2 in Murine Prostate Cancer TRAMP C1 Cells by Natural Phytochemicals Z-Ligustilide and Radix Angelica Sinensis via Promoter CpG Demethylation. Chem. Res. Toxicol. 26 (3), 477–485. 10.1021/tx300524p Suh Y. Afaq F. Khan N. Johnson J. J. Khusro F. H. Mukhtar H. (2010). Fisetin Induces Autophagic Cell Death through Suppression of mTOR Signaling Pathway in Prostate Cancer Cells. Carcinogenesis 31 (8), 1424–1433. 10.1093/carcin/bgq115 Sun B. L. Cai E. B. Zhao Y. Wang Y. Yang L. M. Wang J. Y. (2021). Arctigenin Triggers Apoptosis and Autophagy via PI3K/Akt/mTOR Inhibition in PC-3M Cells. Chem. Pharm. Bull. (Tokyo) 69 (5), 472–480. 10.1248/cpb.c21-00021 Sun H. Zhang A. H. Liu S. B. Qiu S. Li X. N. Zhang T. L. (2018). Cell Metabolomics Identify Regulatory Pathways and Targets of Magnoline against Prostate Cancer. J. Chromatogr. B Analyt Technol. Biomed. Life Sci. 1102–1103, 143–151. 10.1016/j.jchromb.2018.10.017 Swami S. Krishnan A. V. Moreno J. Bhattacharyya R. S. Gardner C. Brooks J. D. (2009). Inhibition of Prostaglandin Synthesis and Actions by Genistein in Human Prostate Cancer Cells and by Soy Isoflavones in Prostate Cancer Patients. Int. J. Cancer 124 (9), 2050–2059. 10.1002/ijc.24161 Tam L. Mcglynn L. M. Traynor P. Mukherjee R. Bartlett J. M. Edwards J. (2007). Expression Levels of the JAK/STAT Pathway in the Transition from Hormone-Sensitive to Hormone-Refractory Prostate Cancer. Br. J. Cancer 97 (3), 378–383. 10.1038/sj.bjc.6603871 Tang Y. Li X. Liu Z. Simoneau A. R. Xie J. Zi X. (2010). Flavokawain B, a Kava Chalcone, Induces Apoptosis via Up-Regulation of Death-Receptor 5 and Bim Expression in Androgen Receptor Negative, Hormonal Refractory Prostate Cancer Cell Lines and Reduces Tumor Growth. Int. J. Cancer 127 (8), 1758–1768. 10.1002/ijc.25210 Tang Y. Parmakhtiar B. Simoneau A. R. Xie J. Fruehauf J. Lilly M. (2011). Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels. Neoplasia 13 (2), 108–119. 10.1593/neo.101092 Taylor B. S. Schultz N. Hieronymus H. Gopalan A. Xiao Y. Carver B. S. (2010). Integrative Genomic Profiling of Human Prostate Cancer. Cancer Cell 18 (1), 11–22. 10.1016/j.ccr.2010.05.026 Thangapazham R. Saenz F. Katta S. Mohamed A. A. Tan S. H. Petrovics G. (2014). Loss of the NKX3.1 Tumorsuppressor Promotes the TMPRSS2-ERG Fusion Gene Expression in Prostate Cancer. BMC Cancer 14 (1), 16. 10.1186/1471-2407-14-16 Theurillat J. P. Udeshi N. D. Errington W. J. Svinkina T. Baca S. C. Pop M. (2014). Prostate Cancer. Ubiquitylome Analysis Identifies Dysregulation of Effector Substrates in SPOP-Mutant Prostate Cancer. Science 346 (6205), 85–89. 10.1126/science.1250255 Thirugnanam S. Xu L. Ramaswamy K. Gnanasekar M. (2008). Glycyrrhizin Induces Apoptosis in Prostate Cancer Cell Lines DU-145 and LNCaP. Oncol. Rep. 20 (6), 1387–1392. 10.3892/or_00000157 Ting H. Deep G. Kumar S. Jain A. K. Agarwal C. Agarwal R. (2016). Beneficial Effects of the Naturally Occurring Flavonoid Silibinin on the Prostate Cancer Microenvironment: Role of Monocyte Chemotactic Protein-1 and Immune Cell Recruitment. Carcinogenesis 37 (6), 589–599. 10.1093/carcin/bgw039 Titus M. A. Schell M. J. Lih F. B. Tomer K. B. Mohler J. L. (2005). Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer. Clin. Cancer Res. 11 (13), 4653–4657. 10.1158/1078-0432.CCR-05-0525 Tomkins G. M. (1957). The Enzymatic Reduction of delta 4-3-ketosteroids. J. Biol. Chem. 225 (1), 13–24. 10.1016/S0002-9610(34)90209-910.1016/s0021-9258(18)64906-3 Tomlins S. A. Rhodes D. R. Perner S. Dhanasekaran S. M. Mehra R. Sun X. W. (2005). Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer. Science 310 (5748), 644–648. 10.1126/science.1117679 Torre L. A. Bray F. Siegel R. L. Ferlay J. Lortet-Tieulent J. Jemal A. (2015). Global Cancer Statistics, 2012. CA Cancer J. Clin. 65 (2), 87–108. 10.3322/caac.21262 Trang N. T. Wanner M. J. Phuong le. V. N. Koomen G. J. Dung N. X. (1993). Thymoquinone from Eupatorium Ayapana. Planta Med. 59 (1), 99. 10.1055/s-2006-959619 Turan I. Demir S. Kilinc K. Burnaz N. A. Yaman S. O. Akbulut K. (2017). Antiproliferative and Apoptotic Effect of Morus Nigra Extract on Human Prostate Cancer Cells. Saudi Pharm. J. 25 (2), 241–248. 10.1016/j.jsps.2016.06.002 Twillie D. A. Eisenberger M. A. Carducci M. A. Hseih W. S. Kim W. Y. Simons J. W. (1995). Interleukin-6: a Candidate Mediator of Human Prostate Cancer Morbidity. Urology 45 (3), 542–549. 10.1016/S0090-4295(99)80034-X Unni E. Sun S. Nan B. McPhaul M. J. Cheskis B. Mancini M. A. (2004). Changes in Androgen Receptor Nongenotropic Signaling Correlate with Transition of LNCaP Cells to Androgen independence. Cancer Res. 64 (19), 7156–7168. 10.1158/0008-5472.CAN-04-1121 Vanella L. Di Giacomo C. Acquaviva R. Barbagallo I. Cardile V. Kim D. H. (2013). Apoptotic Markers in a Prostate Cancer Cell Line: Effect of Ellagic Acid. Oncol. Rep. 30 (6), 2804–2810. 10.3892/or.2013.2757 Vaz C. V. Rodrigues D. B. Socorro S. Maia C. J. (2015). Effect of Extracellular Calcium on Regucalcin Expression and Cell Viability in Neoplastic and Non-neoplastic Human Prostate Cells. Biochim. Biophys. Acta 1853 (10 Pt A), 2621–2628. 10.1016/j.bbamcr.2015.07.006 Visakorpi T. Hyytinen E. Koivisto P. Tanner M. Keinänen R. Palmberg C. (1995). In Vivo amplification of the Androgen Receptor Gene and Progression of Human Prostate Cancer. Nat. Genet. 9 (4), 401–406. 10.1038/ng0495-401 Vitali F. Pennisi G. Attaguile G. Savoca F. Tita B. (2011). Antiproliferative and Cytotoxic Activity of Extracts from Cistus Incanus L. And Cistus Monspeliensis L. on Human Prostate Cell Lines. Nat. Prod. Res. 25 (3), 188–202. 10.1080/14786410802583148 von Eyben F. Kiljunen T. Kangasmaki A. Kairemo K. von Eyben R. Joensuu T. (2015). Management of Advanced Prostate Cancer. Ann. Oncol. 26 (11), 178–182. 10.1093/annonc/mdv327 Wadosky K. M. Koochekpour a. S. (2016). Molecular Mechanisms Underlying Resistance to Androgen Deprivation Therapy in Prostate Cancer. Oncotarget 27, 64447–64470. 10.18632/oncotarget.10901 Wang J. Eltoum I. E. Lamartiniere C. A. (2004). Genistein Alters Growth Factor Signaling in Transgenic Prostate Model (TRAMP). Mol. Cel Endocrinol 219 (1–2), 171–180. 10.1016/j.mce.2003.12.018 Wang J. L. Chou C. T. Liang W. Z. Yeh J. H. Kuo C. C. Lee C. Y. (2016a). Effect of 2,5-dimethylphenol on Ca(2+) Movement and Viability in PC3 Human Prostate Cancer Cells. Toxicol. Mech. Methods 26 (5), 327–333. 10.3109/15376516.2016.1158893 Wang L. G. Liu X. M. Chiao J. W. (2006). Repression of Androgen Receptor in Prostate Cancer Cells by Phenethyl Isothiocyanate. Carcinogenesis 27 (10), 2124–2132. 10.1093/carcin/bgl075 Wang P. Henning S. M. Magyar C. E. Elshimali Y. Heber D. Vadgama J. V. (2016b). Green tea and Quercetin Sensitize PC-3 Xenograft Prostate Tumors to Docetaxel Chemotherapy. J. Exp. Clin. Cancer Res. 35 (1), 73. 10.1186/s13046-016-0351-x Wang Q. Grkovic T. Font J. Bonham S. Pouwer R. H. Bailey C. G. (2014). Monoterpene Glycoside ESK246 from Pittosporum Targets LAT3 Amino Acid Transport and Prostate Cancer Cell Growth. ACS Chem. Biol. 9 (6), 1369–1376. 10.1021/cb500120x Wang Q. Li W. Liu X. S. Carroll J. S. Jänne O. A. Keeton E. K. (2007). A Hierarchical Network of Transcription Factors Governs Androgen Receptor-dependent Prostate Cancer Growth. Mol. Cel 27 (3), 380–392. 10.1016/j.molcel.2007.05.041 Wang W. Rayburn E. R. Hao M. Zhao Y. Hill D. L. Zhang R. (2008a). Experimental Therapy of Prostate Cancer with Novel Natural Product Anti-cancer Ginsenosides. Prostate 68 (8), 809–819. 10.1002/pros.20742 Wang W. L. McHenry P. Jeffrey R. Schweitzer D. Helquist P. Tenniswood M. (2008b). Effects of Iejimalide B, a marine Macrolide, on Growth and Apoptosis in Prostate Cancer Cell Lines. J. Cel Biochem 105 (4), 998–1007. 10.1002/jcb.21898 Wang X. Wang B. Zhou L. Wang X. Veeraraghavan V. P. Mohan S. K. (2020). Ganoderma Lucidum Put Forth Anti-tumor Activity against PC-3 Prostate Cancer Cells via Inhibition of Jak-1/STAT-3 Activity. Saudi J. Biol. Sci. 27 (10), 2632–2637. 10.1016/j.sjbs.2020.05.044 Wang Y. Liu Q. Liu Z. Li B. Sun Z. Zhou H. (2012). Berberine, a Genotoxic Alkaloid, Induces ATM-Chk1 Mediated G2 Arrest in Prostate Cancer Cells. Mutat. Res. 734 (1-2), 20–29. 10.1016/j.mrfmmm.2012.04.005 Watson I. R. Takahashi K. Futreal P. A. Chin L. (2013). Emerging Patterns of Somatic Mutations in Cancer. Nat. Rev. Genet. 14 (10), 703–718. 10.1038/nrg3539 Wei R. Ma Q. Zhong G. He J. Sang Z. (2020). Isolation and Characterization of Flavonoid Derivatives with Anti-prostate Cancer and Hepatoprotective Activities from the Flowers of Hosta Plantaginea (Lam.) Aschers. J. Ethnopharmacol 253, 112685. 10.1016/j.jep.2020.112685 Wertz K. (2009). Lycopene Effects Contributing to Prostate Health. Nutr. Cancer 61 (6), 775–783. 10.1080/01635580903285023 Wolfram J. Suri K. Huang Y. Molinaro R. Borsoi C. Scott B. (2014). Evaluation of Anticancer Activity of Celastrol Liposomes in Prostate Cancer Cells. J. Microencapsul 31 (5), 501–507. 10.3109/02652048.2013.879932 Wu Q. Kohli M. Bergen H. R. 3rd Cheville J. C. Karnes R. J. Cao H. (2014). Preclinical Evaluation of the Supercritical Extract of Azadirachta Indica (Neem) Leaves In Vitro and In Vivo on Inhibition of Prostate Cancer Tumor Growth. Mol. Cancer Ther. 13 (5), 1067–1077. 10.1158/1535-7163.MCT-13-0699 Xiang N. Zhao R. Zhong W. (2009). Sodium Selenite Induces Apoptosis by Generation of Superoxide via the Mitochondrial-dependent Pathway in Human Prostate Cancer Cells. Cancer Chemother. Pharmacol. 63 (2), 351–362. 10.1007/s00280-008-0745-3 Xiao D. Zeng Y. Prakash L. Badmaev V. Majeed M. Singh S. V. (2011). Reactive Oxygen Species-dependent Apoptosis by Gugulipid Extract of Ayurvedic Medicine Plant Commiphora Mukul in Human Prostate Cancer Cells Is Regulated by C-Jun N-Terminal Kinase. Mol. Pharmacol. 79 (3), 499–507. 10.1124/mol.110.068551 Xing L. Venegas A. M. Chen A. Garrett-Beal L. Boyce B. F. Varmus H. E. (2001). Genetic Evidence for a Role for Src Family Kinases in TNF Family Receptor Signaling and Cell Survival. Genes Dev. 15 (2), 241–253. 10.1101/gad.840301 Xu L. Wei Y. Reboul J. Vaglio P. Shin T. H. Vidal M. (2003). BTB Proteins Are Substrate-specific Adaptors in an SCF-like Modular Ubiquitin Ligase Containing CUL-3. Nature 425 (6955), 316–321. 10.1038/nature01985 Xu T. Li T. Zhang Y. Huan S. Cui T. Sun L. (2017). Inhibition of Akt/NF-κB/survivin Pathway by Embelin on Castration-Resistant Prostate Cancer Cells. Oncotarget 34, 3700–3710. 10.1038/onc.2014.302 Xu Y. M. Liu M. X. Grunow N. Wijeratne E. M. Paine-Murrieta G. Felder S. (2015). Discovery of Potent 17β-Hydroxywithanolides for Castration-Resistant Prostate Cancer by High-Throughput Screening of a Natural Products Library for Androgen-Induced Gene Expression Inhibitors. J. Med. Chem. 58 (17), 6984–6993. 10.1021/acs.jmedchem.5b00867 Yaacob N. S. Hamzah N. Nik Mohamed Kamal N. N. Zainal Abidin S. A. Lai C. S. Navaratnam V. (2010). Anticancer Activity of a Sub-fraction of Dichloromethane Extract of Strobilanthes Crispus on Human Breast and Prostate Cancer Cells In Vitro . BMC Complement. Altern. Med. 10 (1), 1–14. 10.1186/1472-6882-10-42 Yan J. Katz A. (2010). PectaSol-C Modified Citrus Pectin Induces Apoptosis and Inhibition of Proliferation in Human and Mouse Androgen-dependent and- Independent Prostate Cancer Cells. Integr. Cancer Ther. 9 (2), 197–203. 10.1177/1534735410369672 Yang C. Gundala S. R. Mukkavilli R. Vangala S. Reid M. D. Aneja R. (2015). Synergistic Interactions Among Flavonoids and Acetogenins in Graviola (Annona Muricata) Leaves Confer protection against Prostate Cancer. Carcinogenesis 36 (6), 656–665. 10.1093/carcin/bgv046 Yang H. Landis-Piwowar K. R. Lu D. Yuan P. Li L. Reddy G. P. (2008). Pristimerin Induces Apoptosis by Targeting the Proteasome in Prostate Cancer Cells. J. Cel Biochem 103 (1), 234–244. 10.1002/jcb.21399 Yang J. Fizazi K. Peleg S. Sikes C. R. Raymond A. K. Jamal N. (2001). Prostate Cancer Cells Induce Osteoblast Differentiation through a Cbfa1-dependent Pathway. Cancer Res. 61 (14), 5652–5659. 10.1016/S0165-4608(01)00481-2 Yang J. Wang C. Zhang Z. Chen X. Jia Y. Wang B. (2017). Curcumin Inhibits the Survival and Metastasis of Prostate Cancer Cells via the Notch-1 Signaling Pathway. Apmis 125 (2), 134–140. 10.1111/apm.12650 Yang S. H. Yates P. R. Whitmarsh A. J. Davis R. J. Sharrocks A. D. (1998). The Elk-1 ETS-Domain Transcription Factor Contains a Mitogen-Activated Protein Kinase Targeting Motif. Mol. Cel Biol 18 (2), 710–720. 10.1128/MCB.18.2.710 Yap T. A. Smith A. D. Ferraldeschi R. Al-Lazikani B. Workman P. de Bono J. S. (2016). Drug Discovery in Advanced Prostate Cancer: Translating Biology into Therapy. Nat. Rev. Drug Discov. 15 (10), 699–718. 10.1038/nrd.2016.120 Yin P. Kawamura T. He M. Vanaja D. K. Young C. Y. (2009). Phenethyl Isothiocyanate Induces Cell Cycle Arrest and Reduction of Alpha- and Beta-Tubulin Isotypes in Human Prostate Cancer Cells. Cell Biol Int 33 (1), 57–64. 10.1016/j.cellbi.2008.09.013 Yoon Y. J. Kim Y. H. Lee Y. J. Choi J. Kim C. H. Han D. C. (2019). 2'-Hydroxycinnamaldehyde Inhibits Proliferation and Induces Apoptosis via Signal Transducer and Activator of Transcription 3 Inactivation and Reactive Oxygen Species Generation. Cancer Sci. 110 (1), 366–378. 10.1111/cas.13852 Yu Z. Xu J. Shao M. Zou J. (2020). Germacrone Induces Apoptosis as Well as Protective Autophagy in Human Prostate Cancer Cells. Cancer Manag. Res. 12, 4009–4016. 10.2147/cmar.S250522 Yuan H. Pan Y. Young C. Y. (2004). Overexpression of C-Jun Induced by Quercetin and Resverol Inhibits the Expression and Function of the Androgen Receptor in Human Prostate Cancer Cells. Cancer Lett. 213 (2), 155–163. 10.1016/j.canlet.2004.04.003 Zabaiou N. Fouache A. Trousson A. Buñay-Noboa J. Marceau G. Sapin V. (2019). Ethanolic Extract of Algerian Propolis Decreases Androgen Receptor Transcriptional Activity in Cultured LNCaP Cells. J. Steroid Biochem. Mol. Biol. 189, 108–115. 10.1016/j.jsbmb.2019.02.016 Zeng Q. Zeng Y. Nie X. Guo Y. Zhan Y. (2020). Britanin Exhibits Potential Inhibitory Activity on Human Prostate Cancer Cell Lines through PI3K/Akt/NF-Κb Signaling Pathways. Planta Med. 86 (18), 1401–1410. 10.1055/a-1211-4656 Zeng Y. Yang Y. (2018). Piperine Depresses the Migration Progression via Downregulating the Akt/mTOR/MMP-9 S-ignaling P-athway in DU145 C-ells. Mol. Med. Rep. 17 (5). 10.3892/mmr.2018.8653 Zengerling F. Azoitei A. Herweg A. Jentzmik F. Cronauer M. V. (2016). Inhibition of IGF-1R Diminishes Transcriptional Activity of the Androgen Receptor and its Constitutively Active, C-Terminally Truncated Counterparts Q640X and AR-V7. World J. Urol. 34 (5), 633–639. 10.1007/s00345-015-1674-5 Zhang C. Shu L. Kim H. Khor T. O. Wu R. Li W. (2016). Phenethyl Isothiocyanate (PEITC) Suppresses Prostate Cancer Cell Invasion Epigenetically through Regulating microRNA-194. Mol. Nutr. Food Res. 60 (6), 1427–1436. 10.1002/mnfr.201500918 Zhang C. Su Z. Y. Khor T. O. Shu L. Kong A. N. (2013). Sulforaphane Enhances Nrf2 Expression in Prostate Cancer TRAMP C1 Cells through Epigenetic Regulation. Biochem. Pharmacol. 85 (9), 1398–1404. 10.1016/j.bcp.2013.02.010 Zhang L. Y. Wu Y. L. Gao X. H. Guo F. (2014). Mitochondrial Protein Cyclophilin-D-Mediated Programmed Necrosis Attributes to Berberine-Induced Cytotoxicity in Cultured Prostate Cancer Cells. Biochem. Biophys. Res. Commun. 450 (1), 697–703. 10.1016/j.bbrc.2014.06.039 Zhang P. Wang D. Zhao Y. Ren S. Gao K. Ye Z. (2017). Intrinsic BET Inhibitor Resistance in SPOP-Mutated Prostate Cancer Is Mediated by BET Protein Stabilization and AKT-mTORC1 Activation. Nat. Med. 23(9), 1055–1062. 10.1038/nm.4379 Zhang X. Haney K. M. Richardson A. C. Wilson E. Gewirtz D. A. Ware J. L. (2010b). Anibamine, a Natural Product CCR5 Antagonist, as a Novel lead for the Development of Anti-prostate Cancer Agents. Bioorg. Med. Chem. Lett. 20 (15), 4627–4630. 10.1016/j.bmcl.2010.06.003 Zhang X. Yeung E. D. Wang J. Panzhinskiy E. E. Tong C. Li W. (2010a). Isoliquiritigenin, a Natural Anti-oxidant, Selectively Inhibits the Proliferation of Prostate Cancer Cells. Clin. Exp. Pharmacol. Physiol. 37 (8), 841–847. 10.1111/j.1440-1681.2010.05395.x Zhang X. Bi L. Ye Y. Chen J. (2014). Formononetin Induces Apoptosis in PC-3 Prostate Cancer Cells through Enhancing the Bax/Bcl-2 Ratios and Regulating the p38/Akt Pathway. Nutr. Cancer 66 (4), 656–661. 10.1080/01635581.2014.894098 Zhao D. Lin F. Wu X. Zhao Q. Zhao B. Lin P. (2012). Pseudolaric Acid B Induces Apoptosis via Proteasome-Mediated Bcl-2 Degradation in Hormone-Refractory Prostate Cancer DU145 Cells. Toxicol. Vitro 26 (4), 595–602. 10.1016/j.tiv.2012.02.004 Zhao F. Huang W. Zhang Z. Mao L. Han Y. Yan J. (2016). Triptolide Induces Protective Autophagy through Activation of the CaMKKβ-AMPK Signaling Pathway in Prostate Cancer Cells. Oncotarget 7 (5), 5366–5382. 10.18632/oncotarget.6783 Zhao Y. Cheng X. Wang G. Liao Y. Qing C. (2020). Linalool Inhibits 22Rv1 Prostate Cancer Cell Proliferation and Induces Apoptosis. Oncol. Lett. 20 (6), 289. 10.3892/ol.2020.12152 Zheng J. Wang J. Wang Q. Zou H. Wang H. Zhang Z. (2020). Targeting Castration-Resistant Prostate Cancer with a Novel RORγ Antagonist Elaiophylin. Acta Pharmaceutica Sinica B 10, 2313–2322. 10.1016/j.apsb.2020.07.001 Zhou Y. Liu Y. E. Cao J. Zeng G. Shen C. Li Y. (2009). Vitexins, Nature-Derived Lignan Compounds, Induce Apoptosis and Suppress Tumor Growth. Clin. Cancer Res. 15 (16), 5161–5169. 10.1158/1078-0432.CCR-09-0661 Zhu Y. Liu C. Nadiminty N. Lou W. Tummala R. Evans C. P. (2013). Inhibition of ABCB1 Expression Overcomes Acquired Docetaxel Resistance in Prostate Cancer. Mol. Cancer Ther. 12 (9), 1829–1836. 10.1158/1535-7163.MCT-13-0208 Zhuang M. Calabrese M. F. Liu J. Waddell M. B. Nourse A. Hammel M. (2009). Structures of SPOP-Substrate Complexes: Insights into Molecular Architectures of BTB-Cul3 Ubiquitin Ligases. Mol. Cel 36 (1), 39–50. 10.1016/j.molcel.2009.09.022 Zingue S. Gbaweng Yaya A. J. Michel T. Ndinteh D. T. Rutz J. Auberon F. (2019). Bioguided Identification of Daucosterol, a Compound that Contributes to the Cytotoxicity Effects of Crateva Adansonii DC (Capparaceae) to Prostate Cancer Cells. J. Ethnopharmacol 247, 112251. 10.1016/j.jep.2019.112251 Zingue S. Rutz J. Maxeiner S. Ndinteh D. T. Chun F. K.-H. Jüngel E. (2021). In Vitro pro-apoptotic and Anti-migratory Effects of Treculia Africana Decne. (Moraceae) and Entandrophragma Angolense Welw (Meliaceae) Extracts on Prostate Cancer Cells. J. Herbal Med. 28, 100443. 10.1016/j.hermed.2021.100443