The AR, also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a member of the steroid hormone group (nuclear receptors) that is activated by binding any of the androgenic hormones, including testosterone and 5α-dihydrotestosterone (DHT) in the cytoplasm and then translocating into the nucleus. The AR is most closely related to the progesterone receptor, and progestins in higher dosages can block the AR. Androgens are critical for the development and differentiation of the male sexual phenotype (Tan et al., 2015).

Testosterone, the most active androgens in males, is produced by Leydig cells in the testis. The testes are responsible for the production of 90–95% of circulating androgens, and the adrenal gland contributes the remainder. The secretion of testosterone from these cells is regulated by luteinizing hormone (LH) from the anterior pituitary gland. Serum sex hormone-binding globulin (SHBG) and albumin are responsible for transferring testosterone in the bloodstream. In target cells as well as prostate cells, 5α-reductase transforms testosterone into its active form, DHT. They can regulate the AR’s transcriptional activity. The normal function, development, and maintenance of the prostate gland are dependent on DHT acting through AR. So, androgens have an expanding role in maintaining prostate homeostasis, and under abnormal conditions, they contribute to the development of prostate cancer. Around 80–90% of cases of prostate cancers are required to measure androgen at initial diagnosis, and endocrine therapy of prostate cancer is directed toward the reduction of serum androgens and inhibition of AR (Wang et al., 2018; Kokal et al., 2020).

ADT is the mainstay of treatment against metastatic and advanced prostate cancer and is also used as an adjuvant to local treatment of high-risk diseases. Current ADT includes surgical methods such as surgical orchiectomy and medical castration including GnRH agonists and antagonists targeting the hypothalamic–pituitary axis, blocking steroid production by enzymatic inhibition, antiandrogens that inhibit binding to the AR (Komura et al., 2018).

Approximately 80–90% of patients with the metastatic disease showed quite proper clinical and biochemical responses achieving a rapid decline in serum prostate-specific antigen (PSA) at the beginning of endocrine therapy (Amaral et al., 2012) and depletion of serum testosterone to “castrate” levels (<50 ng/ml), resulting in induction of apoptosis signaling in malignant prostate cells and temporal suppression of disease (Kahn et al., 2014). However, a significant proportion of patients progress to CRPC, measured by rising serum PSA, or appearance of metastases, after an average remission time of 2–3 years. CRPC, which was previously called hormone-refractory prostate cancer, carries a poor prognosis, and it is estimated that the mean survival time of patients is 9–36 months (Čapoun et al., 2016). Approximately 90% of patients with CRPC will face bone metastases, resulting in severe pain, pathologic fractures, and/or bone marrow failure (Penticuff and Kyprianou, 2016).

The progression of tumor growth and development of metastases regardless of androgen ablation to castrate levels are caused by the utilization of several modifying cell pathways.

Understanding the mechanisms underlying the progression of prostate cancer from hormone-sensitive to castration-resistant is the key to develop future therapy. Androgens and AR play a significant role in the development of CRPC. Approaching new therapeutic landscapes into effective targets will be a promising strategy in maximizing effectiveness and increasing survival in patients with CRPC (Obinata et al., 2020).

The prostate tumor microenvironment is complex and heterogeneous comprising several factors, which are directly or indirectly involved in the progression of the tumor (Torrealba et al., 2017). Furthermore, this tumor microenvironment constitutes cellular entities, such as cancer-associated fibroblasts, cell infiltrates, and extracellular matrix (ECM) (Gurel et al., 2014). Fibroblasts partake in ECM formation and release collagen types I and III (Gabbiani, 2003). However, because of the inappropriate positioning of cancer, their biopsy sampling has always been a hurdle (Bjurlin and Taneja, 2014). The growth of prostatic cancer and metastasis is linked to the balance between the neoplastic cells and constituents of the stroma (Torrealba et al., 2017). The fibroblasts associated with cancer have been acting as the source of reactive stroma stimulated by PCa cells (Gabbiani, 2003; Desmoulière et al., 2005; Schauer et al., 2009; Hansen et al., 2010). The growth factors are released due to the regular destruction and formation of ECM. Also, the secretion of fibroblasts mediates the healing process. Furthermore, the release of an excessive amount of reactive oxygen species and tenascin C by cancer-associated fibroblasts promotes the proliferation and migration of prostate cancer (Schauer and Rowley, 2011). These cancer-associated fibroblasts are characterized by the presence of molecular markers, which include fibroblast activation protein, PDGFR-β, and fibroblast-specific protein-1 (Orr et al., 2011). The presence of these markers determines the heterogeneity and the origin of cancer-associated fibroblasts. The prostatic tumorigenesis is not dependent on the angiogenesis upregulation (Melegh and Oltean, 2019). Blood vessel formation plays an important role in cell viability and growth. The formation of immature leaky blood vessels characterizes the tumor vasculature. The interaction between the tumor cells and stromal endothelial cells increases the vascular endothelial growth factor (VEGF). VEGF plays an important role in the stimulation of metastatic activity and acts via suppression of androgen receptor and transcriptional activity. This suggests that their inhibition could stop the further replication of PCa (Amankwah et al., 2012; Tomić et al., 2012). Macrophages play an important role in tumor progression. They infiltrate into the tumor tissue and reside in the metastatic nodules (Doak et al., 2018; Loyher et al., 2018; Lin et al., 2019). The prostate-derived parathyroid hormone-related protein mediated an increase in tumor-associated macrophages (Soki et al., 2012). This parathyroid hormone-related protein recruits more myeloid cells and osteoblast-produced chemokine ligand 2 (Zhang et al., 2010). The PCa cells are also involved in the GLS1 protein expression. Due to PCa cells, the expression of GLS1 protein is enhanced compared to the benign glandular epithelium (Myint et al., 2021). A study was conducted to evaluate the importance of lysophosphatidic acid receptor 1 (LPAR1) in PCa (Shi et al., 2020). It was found that the level of LPAR1 is downregulated in patients with PCa. The role of LPAR1 can also be traced back to its involvement in the biological process; it handles the improvement of the tumor microenvironment. In the oncomine database analysis, it was observed that in the lymphoma region, the LPAR1 was over-expressed, while it was poorly expressed in the prostate, bladder, and other regions of cancer.

Inflammation has also been linked to the development of PCa, while chronic inflammation is linked to the development of malignant prostate tissue (Lu et al., 2006; Stark et al., 2015). The major region for an association of PCa and chronic inflammation is still under doubt. This may be accounted for the ongoing genotoxic stress from DNA damage that takes place during oncogenesis and may act as the major contributor (Sprung et al., 2015; Udensi and Tchounwou, 2016).

The extracellular vesicles also play an inevitable role in the paracrine communication between the cancer cells and CAFs in the prostate tumor microenvironment (Vlaeminck-Guillem, 2018). The prostate cancer cells release exosomes that harbor transforming growth factor-beta 1 (TGF-β1), which is involved in the induction of myofibroblast (MFB) transition. The disruption of PCa cells causes the loss of stroma together with their growth promotion characteristics (Webber et al., 2014). The microRNA-409, secreted by cancer-associated fibroblasts, inhibits the translation of tumor suppressor genes and helps the tumor to invade (Josson et al., 2014).

Rettig et al. (2008) showed that the extract of pomegranate results in the inhibition of the growth of androgen-independent PCa via a nuclear factor-KB-dependent mechanism. Shenouda et al. (2007) showed that an extract from the bark of an African plum tree, Pygeum africanum, inhibited the proliferation of PC-3 and LNCaP cells and induced apoptosis via downregulation of ERa and PKCa protein, which displayed a virtuous binding ability to both LNCaP human ARs and mouse uterine estrogen receptors.

Researchers have demonstrated the anti-PCa properties of several natural products such as curcumin, resveratrol, lycopene, apigenin, quercetin, fisetin, luteolin, kaempferol, genistein, berberine, ursolic acid, eugenol, gingerol, ellagic acid, silibinin A, silibinin B, and epicatechin-3-gallate, both in vitro and in vivo, by their effects on cyclooxygenases, lipoxygenases, and phospholipase A2 (Sarkar et al., 2010; Tewari et al., 2019; Fontana et al., 2020; Marzocco et al., 2021). The chemical structures of some important anti-PCa phytochemical compounds are depicted in Figure 1.

Embelin is a potential natural therapeutic agent used to prevent and treat CRPC. It demonstrated its ability to suppress numerous signaling pathways, mostly involved in the formation of cancer, and majorly via blocking of XIAP and caspase-9 interaction (Prabhu et al., 2018).

Curcumin is a yellow color pigment found in turmeric and derived from the plant Curcuma longa. It has been shown to enhance TNF and radiation-induced apoptosis in human PCa cells. It inhibits NF_kB by the suppression of I_kB phosphorylation, which downregulates the anti-apoptotic gene products and activates the caspases (Sainz et al., 2008). Like curcumin, pieces of evidence showed that polyphenols such as epicatechin-3-gallate (ECG) and epigallocatechin-3-gallate (EGCG) present in green tea can inhibit the methylation of DNA, which induces anticancer effects with potent anti-PCa potential (Kallifatidis et al., 2016; Wang et al., 2020). Camptothecin, a cytotoxic alkaloid, derived from the plant Camptotheca acuminata, exhibited noteworthy anti-proliferative activity via topoisomerase-I inhibition. Vinblastine, a vinca alkaloid, derived from the plant Catharanthus roseus, binds to tubulin and inhibits the microtubule assembly. Paclitaxel (Taxol), a mitotic inhibitor, derived from Taxus brevifolia, is used to treat patients with several forms of cancers (Mishra and Tiwari, 2011).

Quercetin, a penta-hydroxylated flavanol compound, found in apples, tea, onions, capers, and tomatoes, exhibited potent chemopreventive activities and cytotoxic potential by inhibiting the function of androgen receptors in LNCaP prostate cancer cells (Xing, 2001). Fisetin, a dietary flavonoid compound, has been found to exhibit cancer growth inhibition ability via alterations in the cell cycle and induce apoptosis. Fisetin, when reacting with LNCaP cells, causes PCa suppression via the G1-phase of cell cycle arrest and modulates the networking of CKI-cyclin-CDK (Lall et al., 2016). Luteolin, also a flavonoid compound, significantly inhibits the proliferation of PCa cells via induction of apoptosis in LNCaP cells (Roell and Baniahmad, 2011). Atraric acid and N-butyl-benzene sulfonamide are the two novel AR antagonists, extracted from an evergreen tree P. africanum, that have been used in combinational therapy for the treatment of PCa (Chiu and Lin, 2008).

According to literature survey, it has been found that several natural products and their derivatives/metabolites can selectively target the signaling pathways that are concerned with the expansion of cancer growth. The major signaling pathways modulated via phytochemicals in the management of CRPC (Fontana et al., 2020) are described in Figure 2.

Shamaladevi et al. (2013) showed that ericifolin (EF) or eugenol, extracted from Jamaican pepper berries, Pimenta dioica (allspice), inhibited the proliferation of prostate cancer cells via induction of apoptosis and formation of colonies. Meimetis et al. (2011) displayed in their research that niphatenones A and B, glycerol ether lipids extracted from Niphates digitalis (a marine sponge), inhibited the androgen-induced proliferation of LNCaP prostate cancer cells and acted as lead compounds for the production of newer medications used in the treatment of castration-resistant prostatic adenocarcinoma.

Sadar et al. (2008) showed that sintokamides A to E, extracted from a marine sponge Dysidea sp., inhibited the proliferation of prostate cancer cells via blockage of N-terminus trans-activation of ARs. Galardy et al. (2013) displayed that betulinic acid extracted from white-bark birch trees induced PCa-specific apoptosis via accumulation of poly-ubiquitinated proteins by inhibiting multiple deubiquitinases (DUBs).

Li et al. (2008) showed that the isoflavones present in soybeans inhibited the phosphorylation of Akt and FOXO3a and increased the expression of glycogen synthase kinase-3β (GSK-3β), which resulted in the down-regulation of AR and caused the induction of apoptosis and inhibition of the proliferation of PCa cells. Mori et al. (2006) and Malagarie-Cazenave et al. (2009) showed that capsaicin, a constituent of red peppers, inhibited the development and progression of androgen-independent p53 mutant PCa cells via PI3K and MAPK pathways in prostate LNCaP cells. It also inhibited the TNFα-stimulated degradation of IKBA in PC-3 cells, which has been associated with the inhibition of proteasome activity.

Cha et al. (2005) showed that emodin, extracted from the plant Rheum palmatum, inhibited the proliferation of PCa cells via down-regulation of androgen receptors from Hsp90 and intensification of its interactions with E3 ligase MDM2, thereby endorsing the proteasome-mediated deprivation of AR in LNCaP cells.

Curcumin has various numbers of pharmacological activities such as antioxidant properties, anti-inflammatory action, capability to control the cell cycle, and stimulation of the process of apoptosis (Shishodia et al., 2007; Wilken et al., 2011). It also has the capacity to modulate autophagy and inhibit tumor angiogenesis and also metastasis in various cancers (Wang et al., 1997; Bar-Sela et al., 2010). The utilization of curcumin in clinical trials is limited due to its hydrophobic profile, instability, low pharmacokinetic profile, and poor water solubility, though it has many other beneficial pharmacological properties (Shoba et al., 2007). So, nanoparticles were developed for the effective delivery of curcumin to improve its efficacy in the treatment of cancers. Nanoparticles are potent to protect drugs from degrading, enhance drug stability, enhance controlled drug release, and also increase pharmacokinetic property and decrease toxicity profile of the drug (De Jong and Borm, 2008; Markman et al., 2013). Docetaxel is usually used in the mainstay treatment of CRPC. Over time, CRPC patients developed resistance against docetaxel, which might also be a reason behind the mortality of patients. Tanaudommongkon et al. (2020) used a few pharmaceutical excipients for the preparation of curcumin nanoparticles such as Miglyol 812 and a surfactant, d-alpha-tocopheryl polyethylene glycol succinate (TPEGS) 1000 (which is derived from vitamin E). The surfactant used in the preparation of nanoparticles has been approved by the Food and Drug Administration (FDA) as the safest excipients that can be employed in preparing many formulations. The inhibition of efflux by allosteric modulation of P-glycoprotein by TPEGS is also a valuable addition to selecting that particular surfactant (Collnot et al., 2010). Nanoparticles encapsulated with curcumin were prepared and characterized for zeta potential, particle size, drug loading, efficiency, differential scanning calorimetry analysis, stability study, and also in vitro studies.

Quercetin shows certain undesirable features that may lead to its poor systemic availability. It has poor bioavailability and water solubility (0.00215 g/l at 25°C to 0.665 g/l at 140°C), and it is quickly metabolized by the body, which can limit its effectiveness as an agent for disease prevention (Ceña et al., 2012). The encapsulation of quercetin with biodegradable nanoparticles and biocompatibility may delay or avert its metabolism in the body and permit for retention of the long-term effect of quercetin in the blood and other tissues. Applying nanotechnology-based quercetin formulations can overcome the undesirable features to its delivery (Srinivas et al., 2010).

To deal with the poor bioavailability and hydrophobicity of quercetin in CRPC, Zhao et al. (2016) conducted in vivo and in vitro studies by encapsulating quercetin in nanomicelles. An encapsulation of 1 mg/ml potentially improves the water solubility of quercetin 450-fold. The in vitro results showed that the IC₅₀ for micellar quercetin formulation was 20 μM, compared to 200 μM of free quercetin. Therefore, the nano-based preparation capably inhibited proliferation and apoptosis in human androgen PCa cell lines. In addition to this, quercetin-loaded micelles in vivo showed higher antitumor efficiency, and proliferation rate decreased by 52.03% in comparison to the control group in the PC-3 xenograft mouse model, likely due to improved accumulation of micellar quercetin at the tumor site through enhanced permeability and retention effects (Zhao et al., 2016). The nanomicelle-based drug delivery system forms a promising and successful pharmaceutical treatment approach for PCa (Figure 4).

As already explained in the Natural Therapeutic Products for CRPC Treatment and Management section, EGCG is having the potential to manage CRPC, but bioavailability is an important concern. Rocha et al. (2011) had encapsulated EGCG in a polysaccharide matrix of gum arabic and maltodextrin and studied its anti-PCa potential in Du145 prostate cancer cells. They found that encapsulated EGCG not only retained the anti-prostate cancer activity by reducing cell viability and apoptosis induction but also had enhanced effects when compared with free EGCG (Rocha et al., 2011). Khan et al. (2014) had prepared the oral formulation of chitosan nanoparticles, which were encapsulated with epigallocatechin-3-gallate, and these chitosan-EGCG nanoparticles of < 200-nm diameter were then assessed for antitumor potential in athymic nude mice (subcutaneously implanted with 22 Rν1 tumor xenografts). Results indicated that the chitosan-EGCG nanoparticles were the better anti-PCa agent, as compared to EGCG alone or control groups, via modulation of multiple pathways. In the intestinal fluid, the release of EGCG was faster, thus addressing the bioavailability issue (Khan et al., 2014).

Combination therapies are quite trendy when dealing with chronic diseases because of synergy effects. Chen et al. (2020) had encapsulated EGCG with low doses of docetaxel (DTX) in the nanoparticles based on TPGS-conjugated hyaluronic acid and fucoidan. Out of multiple combinations, they found that an EGCG/DTX ratio 2.00:0.20 mg/ml had better and narrower distribution and significant percentage drug loading efficiencies. In the in vitro studies, they found internalization of these nanoparticles into prostate cancer cells, thus making the combination more target specific. Furthermore, in vivo studies indicated an increase in M30 protein expression with attenuated tumor growth, without affecting organs (Chen et al., 2020).

Lu et al. (2013) had prepared stable micelles with polyethylene glycol 5000 and embelin and then encapsulated paclitaxel in it to make a combination therapy. The nanomicelles were in the range of 20–30 nm. In vitro studies suggested an efficient uptake of these nanomicelles in the tumor site along with the slow release of paclitaxel. Furthermore, these nanomicelles exhibited much better cytotoxicity than individual drugs when tested in many tumor cell lines including DU145 and PC-3. In vivo studies suggested that these nanomicelles exhibited a significant safety profile with selective uptake in the tumor site, minimal movement in sensitive organs like the liver and spleen, and a maximum tolerated dose of 100–120 mg of paclitaxel/kg in mice. Overall, this combination of embelin and paclitaxel nanomicelles offered superior anti-prostate cancer activity as compared to paclitaxel in mouse models of prostate cancer (Lu et al., 2013). Danquah et al. (2009) had prepared the nanomicelles of polyethylene glycol-b-polylactic acid and encapsulated embelin and bicalutamide in them. They performed in vitro experiments on prostate cancer cell lines, namely, LNCaP and C4-2, while the in vivo studies were performed on BALB/C nude mice with LNCaP xenografts. This combination of embelin and bicalutamide had shown synergism in C4-2 with slight antagonism in the case of the LNCaP cell line. Furthermore, the aqueous solubility of this combination was increased by more than 60-fold in the nanomicelle form. Results from the in vivo studies also suggested that the combination in nanomicelle form was much better in regressing these hormone-refractory tumors (Danquah et al., 2009).

Saneja et al. (2017) had prepared nanoparticles of betulinic acid with polylactide-co-glycolide-monomethoxy polyethylene glycol and then studied it against the PANC-1 tumor cell line. The nanoparticles were approximately 147 nm in size and spherical. These betulinic acid nanoparticles were found to have an enhanced half-life by approximately 7.21-fold. Furthermore, the cytotoxic effect was also enhanced in the nanoparticle form, and it was seen because of improvement in apoptotic effect, mitochondrial membrane potential loss, high ROS level, and cell cycle arrest (Saneja et al., 2017).

Though nanoparticles of other natural anti-prostate cancer (anti-PCa) agents were also prepared, those nanoparticles were not discussed here because, to the best of our knowledge, the activity studied for the nanoparticles in those articles was not anti-PCa, for example, fisetin nanoparticles (Kadari et al., 2017), luteolin (Majumdar et al., 2014; Li et al., 2020), eugenol (Majeed et al., 2014), capsaicin (Elkholi et al., 2014; Peng et al., 2014; Lv et al., 2017; Hazem et al., 2021; Kunjiappan et al., 2021), and emodin (Sevilla et al., 2009; Wang et al., 2014; Wu et al., 2017; Jänicke et al., 2021). So, further research can be done to analyze the anti-prostate cancer potential for these nanoformulations. To the best of our knowledge, there are natural products like atraric acid, niphatenones A and B, sintokamides A to E, etc. for which nanoformulations are not yet designed.