PCa is the second most common cancer in males and the fifth-greatest cause of cancer mortality in 2020, with an anticipated 1.4 million new cases and 375,000 deaths globally (Figure 1) (Lin et al., 2018; Sung et al., 2021). It is considered the second leading cause of cancer-related male fatalities and the most common noncutaneous malignancy in males, with more than 160,000 new cases reported in 2017 in the United States (Zhu et al., 2015; Howlader et al., 2017; Teo et al., 2019). According to the GLOBOCAN database, in 2018, an estimated 1.2 million new cases of PCa were recorded worldwide, with developed nations having a greater prevalence. Moreover, the global burden is expected to increase to over 2.3 million and 7,40,000 deaths by 2040 (Ferlay et al., 2018; Rawla, 2019; Culp et al., 2020). PCa is prevalent in almost all major countries and is the leading cancer-related cause of death in males in over 100 nations after lung cancer (112 of 185). The incidence rate ranges from 6.3 to 110.4 per 100,000 males across countries. The higher rates were observed in Northern and Western Europe, the Caribbean, Australia/New Zealand, Northern America, and Southern Africa, whereas the lowest rates were found in Asia and Northern Africa. Previous research studies have suggested that African-American males have the highest prevalence of PCa worldwide and are more prone than other racial and ethnic groups to get the disease at a younger age (Kheirandish and Chinegwundoh, 2011). The higher rates may indicate a greater disease incidence and higher rates of PCa than other places across the globe (Wild et al., 2020; Sung et al., 2021). For a prevalent illness like PCa, little is known about its genesis, and only a few risk factors have been discovered (Lin et al., 2021). Several factors are responsible for changes in its prevalence at the regional level due to changes in the susceptibility of different population groups to environmental risk factors, including racial/ethnic backgrounds, geographical heterogeneity, advancing age and an intact hypothalamic-pituitary-gonadal axis, family history, genetic mutations (e.g., BRCA1 and BRCA2), and diagnosis and access to good quality treatment (Hoimes and Kelly, 2009; Rebbeck et al., 2013; Shackleton et al., 2021). PCa incidence and death rates differ significantly between ethnic groups, implying ethnic and genetic susceptibility (Shackleton et al., 2021). However, since the 1990s, mortality rates in PCa have declined in most high-income countries, including Northern America, Oceania, and Northern and Western Europe, due to advances in therapeutics and earlier diagnostics using enhanced screening methods (Tsodikov et al., 2017). This diversity in PCa mortality rates throughout the world is partly due to underlying biological disparities in risk and treatment availability. For example, places with higher diagnosis rates of low-grade malignancies and improved treatment choices (such as Northern America and Asia) have lower death rates than those with poor screening rates, concomitant diagnoses of aggressive tumors, and limited treatment choices (such as Sub-Saharan Africa).

Immune cells are key components of the tumor microenvironment associated with tumor progression. T regulatory cells (Tregs), tumor-associated macrophages (TAMs), tumor-infiltrating B lymphocytes (TILs), neutrophils, and myeloid-derived suppressor cells (MDSCs) are part of the infiltrated immune cell of the prostate tumor microenvironment. However, various studies have reported that the progression of PCa is influenced by the tumor-associated immune cells and inflammatory cytokines, such as IL-23 (Ammirante et al., 2010; Si et al., 2013; Calcinotto et al., 2018; Wang et al., 2019; Zhang Z. et al., 2020). TAMs are a major component in the development of PCa, though the specific pathway for the release of cytokines, matrix metalloproteinases, and growth factors is still unknown (Shimura et al., 2000; Arora et al., 2018). Castration resistance is characterized by both hyper- and/or constitutively active androgen receptor expression (AR) in PCa cells toward cellular interactions between stem cells and bone microenvironmental systems (Karamanolakis et al., 2016). The cancer cell dependency on the tumor microenvironment indicates that the noncancer cell component of the tumor can regulate the spread of PCa. However, the immune response from the tumor microenvironment contributing to the development of CRPC is unknown (Calcinotto et al., 2018). The typical prostate gland comprises prostatic ducts surrounded by epithelium and a stroma made up of smooth muscle cells with a few fibroblasts, endothelial cells, and nerve cells. ARs are widely expressed in several normal prostate stromal cell types, including smooth muscle cells, endothelial cells, and epithelial cells (Cunha et al., 1996). Multiple nonmalignant cells, such as fibroblasts, myofibroblasts, endothelial cells, and immune cells, chemokines, cytokines, growth factors, extracellular matrices (ECMs), and matrix-degrading enzymes make up the stromal compartment (Corn, 2012). The connection between the epithelial and stromal sections facilitates the progression of tumors through processes such as ECM reintegration, increasing penetration and releasing soluble growth factors for castrate-resistant growth, and angiogenesis stimulation (Rowley, 1998; Karlou et al., 2010). Immune cells are typical inhabitants and have a protective function against infections that infiltrate healthy prostatic tissue. However, histological investigations have revealed that high-grade PCa is associated with enhanced stromal immune cell infiltration with differences between tumor-stage cell types (Gurel et al., 2014).

One of the factors contributing to PCa progression is androgen binding to androgen receptors. Herein, androgens play a pivotal role in the growth and survival of PCas. Moreover, increased expression of androgen receptors is often observed in CRPC (Gelmann, 2002). Androgen receptor translocates into the nucleus with the aid of ligand binding, where it orchestrates transcription, modulates growth signaling pathways, and dictates programmed cell death, cellular proliferation, and androgen-associated genes (Andersen et al., 2010). PI3K-Akt-mTOR pathway stands at the forefront of the initiation of CRPC, which is essentially triggered by G protein-coupled receptors (GPCR). Accumulating evidence has suggested that perturbations in the PI3K-Akt-mTOR pathway occur in the vast majority of metastatic cancers; hence, PI3K-Akt-mTOR can be a potential therapeutic target (Huang et al., 2018). Phosphatase and tensin homolog (PTEN) has been associated with PI3K-Akt-mTOR triggering in advanced stages of the disease, especially the downregulation of this gene (McMenamin et al., 1999). A previous study has proven that AR is interlinked with PI3K-Akt-mTOR, where combination therapy of AR and PI3K-Akt-mTOR inhibition by EPI-002 and BEZ235 in vitro and in vivo successfully reduced LNCaP95 cell growth and was noted as a potential therapeutic avenue in CRPC (Kato et al., 2016).

Similarly, the JAK/STAT pathway is also a membrane-to-nucleus signaling pathway, which is vital for the development, proliferation, migration, and apoptosis of cells, often triggered by agents, such as cytokines and growth factors (Ramalingam et al., 2017). When triggered, JAKs induce phosphorylation of STAT proteins. Therefore, STATs are dimerized and thereby translocated to the nucleus via importin α-5 and the Ran nuclear import pathway. STATs display a specific stimulation or suppression of transcription of target genes by binding to specific sequences inside the nucleus (Ramalingam et al., 2017). JAK/STAT3 pathway is a well-established prosurvival inducing mechanism, where repression of this pathway reduced the PCa cell growth and induced programmed cell death (Liu et al., 2012). Oncogenes like BRAC induce proliferation and migration via the JAK/STAT3 pathway (Gao et al., 2001). Furthermore, STAT3 activation triggers other genes linked to the cell cycle, angiogenesis, and tumor progression (Dhir et al., 2002; Zhu and Kyprianou, 2008). In various conditions, JAK/STAT3 is a predictor of poor disease prognosis (Liu et al., 2012).

Src signaling has been implicated in promoting growth factors and inflammatory cytokines, such as IL-8, and inducing angiogenesis (Park et al., 2007). Additionally, Src signaling triggers nuclear factor-KB (Nf-KB) and tumor necrosis factors involved in evading apoptosis and promoting bone metastasis of PCa (Park et al., 2007). Targeting Src has immensely slowed down tumor growth and hindered invasion, which can be achieved using the two clinical drugs, dasatinib and saracatinib (Yang et al., 2010; Araujo et al., 2013). Moreover, growth factors, such as IGF-1, IL-6, and EGFR, can individually promote CRPC (Bettedi and Foukas, 2017). Activation of Her-2/neu, a receptor tyrosine kinase, has been observed to increase the growth of CRPC in clinical samples and xenograft models (Wen et al., 2000; Neto et al., 2010). A clinical study on targeting growth factor signaling pathways with the help of cabozantinib and tyrosine kinase inhibitor has achieved a therapeutic advantage in various stages, such as survival devoid of disease progression and marked decrease of metastatic lesions (Smith et al., 2013).

Recent evidence has revealed a regulatory mechanism, that is, crosstalk between AR and Wnt pathway, where suppression of Wnt pathway facilitates reducing AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis in vitro. Further, a correlation between Wnt genes, like WNT5A and LEF1, and metastatic PCa has been observed (Luo et al., 2020). Wnt catenin pathway plays a principal role in homeostasis, proliferation, migration, and cell transitions (Kuhl and Kuhl, 2013). Increased catenin in PCas leads to phosphorylation and inactivation of GSK3 (Chesire and Isaacs, 2003; He et al., 2004). Inclined expression of Wnt is correlated with disease progression and metastasis. Furthermore, FZD4 overexpression favors EMT in CRPC (Polakis, 2007; Gupta et al., 2010).

Long noncoding RNAs (lncRNAs) are a group of transcripts widely employed as diagnostic tools and have received great attention because they are expressed in a more tissue-specific manner. Recent emerging evidence has shown that lncRNAs play vital roles in cancer initiation and progression, including PC progression and AR-related pathways (Ren et al., 2013; Fang et al., 2016). In a very recent study by Yao et al., LINC00675 has been abundantly found in both androgen-insensitive cells and CRPC patients. In the same study, it has been confirmed that LINC00675 binds to GATA2 mRNA and makes GATA2 an activator in the AR signaling mechanism in the nucleus, contributing to both castration resistance and disease progression (Yao et al., 2020). Signaling pathways associated with castration-resistant prostate cancer are illustrated in Figure 2.

An androgen receptor-dependent mechanism of resistance in hormone-naïve PCa leads to castration resistance. Apart from the AR, survival can be achieved and enhanced via cell-intrinsic pathways or progrowth signals from the microenvironment.

Expansion of malignant prostatic cells and normal cells and proliferation of CRPC are extremely dependent on androgens. Consequently, it has been hypothesized that androgens play a fundamental role in prostate tumor genesis. As a result, the main remedial target for PCa is reducing the levels of androgens (Zhou et al., 2015), which is accomplished through ADT. Despite this, severe complications are the resurrection of androgens and elevation of PSA. This condition is called CRPC and is characterized by a loss in the ability to respond to ADT, leading to reappearance of PCa and metastasis (Perlmutter and Lepor, 2007; Hotte and Saad, 2010). The translation of hormone-dependent PCa cells to CRPC is chiefly driven by the upregulation of AR activity. Urbanucci et al. have reported the overexpression of AR receptors in 22–30% of patients with CRPC (Urbanucci et al., 2011; Petrylak, 2013; Coutinho et al., 2016). In another study, Hay et al. have declared that the AR gene mutation was found in 22–30% of CRPC cases (Lobaccaro et al., 2012; Eisermann et al., 2013). Sharifi has shown the metabolic transformation of DHT (dihydrotestosterone). The USFDA has approved docetaxel for the management of CRPC. Similarly, cabazitaxel, another taxol derivative, has been tested in phase III clinical trial against CRPC. Numerous research groups have reported differentially expressed genes and phytochemicals established as inhibitors of identified targets for CRPC (Sharifi, 2013).

Rotimi et al. have conducted differential gene expression analysis of phytoconstituents target for CRPC. Plant-based phytomolecules were subjected to virtual screening toward GUCY1A2 variants. The results have revealed that SYT4, GUCY1A2, and GRIN3A were the most pharmacologically significant genes implicated in the pathogenesis of CRPC in the xenograft model (Rotimi et al., 2019). The docking scores of (8′S)-neochrome and (8′R)-neochrome were −152.102 and −160.75, respectively, when targeting G723S and Q217H. In another report, Cai et al. have observed an elevated expression of the α-subunit of soluble guanylyl cyclases (α-sGC) in hormone-refractory PCa at both the mRNA and protein levels (Krumenacker et al., 2004; Cai et al., 2006). It has been found that α-sGC leads to suppression of apoptosis via accumulation of p53 in the cytoplasm; hence, it is proposed as a target for CRPC. In another approach, Liao et al. have reported the screening of natural products, including terpenes, alkaloids, flavonoids, and polyphenols. Among them, rutaecarpine, obtained from Tetradium ruticarpum (A.Juss.) T.G.Hartley, has been found to exhibit potential effects against CRPC using in vitro and in vivo studies in LNCap and 22 RV1 cell lines and in xenograft models, respectively. The outcomes of western blotting analysis have revealed that AR-V7 and AR-FL were expressed in LNCaP and 22Rv1. Moreover, rutaecarpine has been found to exhibit a dose-dependent downregulated AR-V7 protein expression (Liao et al., 2020). Mendiratta et al. have established the genomic stratagem to manage CRPC using a transcription-based androgen receptor activity signature toward LNCaP cell lines (Mendiratta et al., 2009). AR signature has been employed to determine whether AR activity varies with hormone therapy; progression and oncogenic pathway assays were used to recognize biologic pathways associated with AR activity. The probability of AR activity was 0.13, 0.11, 0.96, and 087 against PC-3, DU-145, LNCaP, and 22Rv PCa cell lines, respectively (Amler et al., 2000; Febbo et al., 2005; Hieronymus et al., 2006). Moreover, these genomic targets served as diagnostic and prognostic biomarkers, and their discovery has been expedited multifold due to NGS technologies (Chen et al., 2013a; Chen et al., 2013b; Shen et al., 2021). Thus, discovering these biomarkers is fundamental for developing diagnostic biosensors (Jiang et al., 2014).

Over the last 40 years, most chemotherapy drugs used to treat cancer originated from natural products. Moreover, phytomolecules may provide various lead structures used as templates to synthesize new, pharmacologically more effective agents (Mann, 2002). Since concomitant side effects, if any, are reported to be mild, plants and their metabolites are considered to be potentially acceptable choices for chemoprevention. It has been shown that several phytocompounds, such as genistein, green tea polyphenols, curcumin, lycopene, and vitamin D, prevent or postpone the onset of PCa or its development to CRPC (Kallifatidis et al., 2016). Basic and applied research are two types of study that are usually separated. Basic research is important for better understanding normal and pathological states, but it does not directly translate this information into therapeutically relevant applications. Based on our understanding of illness formation and progression, applied research aids in the development of novel diagnostic tools or treatments for patients. The major objective of “translational” research is to combine molecular biology advances with clinical trials, bringing research from the bench to the patients’ bedside (Gibbs, 2000; Saijo et al., 2003; Goldblatt and Lee, 2010). Most cancers likely develop due to multiple genetic abnormalities, implying the need for a cocktail of agents against multiple targets in cancer cells or the use of agents with a broad range of targets, which is one of the most critical factors limiting the effectiveness of targeted therapy. The treatment of CRPC patients is still a serious clinical issue. Researchers now have a better knowledge of the mechanisms of CRPC owing to molecular, basic, and translational studies (Amaral et al., 2012). Many clinical trials to assess the efficacy of phytochemicals in human subjects have been undertaken, and they have partially corroborated the encouraging results found in vitro and preclinical models. We will only discuss those clinical studies where the pure phytocompounds or the characterized phytofractions were considered. We have excluded studies on extracts and juices, as they would have deviated content from the theme. Plant-derived constituents showing remarkable anticancer effects against CRPC in clinical trials are discussed as follows.

Resveratrol. Resveratrol is a polyphenol found in nature that has been shown to inhibit PCa growth and development. In several preclinical investigations, resveratrol has been shown to decrease prostate cancer development in vitro and in animal models. Moreover, resveratrol has been found to reduce androgen receptor expression, decrease proliferation, induce apoptosis in PCa cell lines, and improve their ionizing radiation sensitivity (Jasinski et al., 2013). Dietary resveratrol suppresses β-catenin-mediated AR signaling and represses nuclear localization of β-catenin by reducing HIF-1 production, perhaps in a proteasome-independent way, contributing to the reduction of CRPC tumor progression (Mitani et al., 2014). Kjaer et al. have conducted a randomized controlled trial (RCT) using two doses of resveratrol (150 mg or 1,000 mg resveratrol daily) for 4 months in 66 middle-aged men suffering from metabolic syndrome. High-dose resveratrol (1,000 mg daily) treatment for 4 months dramatically reduced blood levels of the androgen precursors androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. However, the prostate size and circulating levels of PSA, testosterone, free testosterone, and dihydrotestosterone were unchanged (Kjaer et al., 2015). Patients with nonmetastatic biochemically recurrent PCa were allocated to escalating doses of MPX (pulverized muscadine grape skin rich in ellagic acid, quercetin, and resveratrol) in cohorts of two patients, with six patients at the maximum dose in the phase I section of this phase I/II trial, which used a modified continuous reassessment technique. The phase I section revealed that the largest dose tested, 4,000 mg/d, was safe, with only grade 1 adverse event being recorded. Even though the phase I population was small and there was no sustained decrease in serum PSA from baseline, the findings show that 4,000 mg/d of muscadine grape skin extract is safe (Paller et al., 2015).

Furthermore, Paller et al. have conducted a randomized, multicenter, placebo-controlled, dose-evaluating phase II trial. The results on 112 biochemically recurrent (BCR) patients were evaluated, revealing that MPX did not significantly improve the prostate-specific antigen doubling time (PSADT) compared with the placebo. Nevertheless, other benefits have been observed in the exploratory analysis (Paller et al., 2018). Further, testing resveratrol’s chemopreventive effects in conjunction with other antioxidants occurring naturally together, such as in grapes, might be beneficial (Singh et al., 2016).

Soy Isoflavone. Incidence rates of PCa are lowest in Asian nations, where soy foods are frequently part of a normal diet (Jian, 2009). In some animal models, physiologically active isoflavones found in soy products, such as genistein, daidzein, equol, and glycitin, prevented PCa (Mahmoud et al., 2014). Antioxidant defense, DNA repair, suppression of angiogenesis and metastasis, potentiation of radio- and chemotherapeutic drugs, and antagonism of estrogen- and androgen-mediated signaling pathways are all involved in soy isoflavone-induced growth arrest and death of PCa cells (Mahmoud et al., 2014). In numerous clinical trials (Table 1), soy isoflavones have been found to reduce PSA levels.

Lycopene. Lycopene, a natural pigment found mostly in the ripe tomato fruits, is gaining popularity in preventing and treating heart disease and cancer (Heber and Lu, 2002). Lycopene’s anticancer actions on PCa cells are mediated via decreasing cell proliferation, inducing apoptosis, stopping the cell cycle, and lowering DNA damage in various investigations (Ivanov et al., 2007; Holzapfel et al., 2013). In vitro studies have shown that a normal physiological concentration of lycopene in culture conditions inhibits the growth of PCa cell lines, which are either androgen-dependent or androgen-independent (Kim et al., 2002; Mirahmadi et al., 2020). A human intervention study has demonstrated that consumption of carotenoid-containing plant products significantly decreased oxidative base damage (Pool-Zobel et al., 1997). In phase II randomized clinical trial, 26 men with newly diagnosed, clinically localized PCa randomly allocated to groups taking 15 mg of lycopene twice daily (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy exhibited reduced PSA, connexin 43, and insulin-like growth factor-1 levels (Kucuk et al., 2001). In an unblinded randomized phase I clinical study, 32 patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for 3 weeks (30 mg lycopene/day), which resulted in higher lycopene levels in prostate tissues and serum, reduction in PSA serum levels, and DNA damage in both prostate and leukocyte cells in prostatectomy (Bowen et al., 2002). In a prospective trial, 20 metastatic HRPC patients were given 10 mg lycopene daily for 3 months and in almost all men, disease progression inversely changed to a lower grade. Moreover, PSA levels were reduced and ECOG function and bone pain improved (Ansari and Gupta, 2004). In phase II clinical trial, 10 mg lycopene per day for 1 year resulted in a reduced PSA velocity in 40 individuals (Barber et al., 2006). Bunker et al. have conducted a randomized, unblinded phase I clinical trial in 81 high-risk Afro-Caribbean patients with neoplasia and found that 30 mg/day of lycopene for 4 months lowers PSA serum concentrations (Bunker et al., 2007). In a phase II research, 46 androgen-independent PC patients were given lycopene (15 mg twice daily), which resulted in a 50% drop in PSA levels; however, the trial showed no clinical benefit for the advanced stage of cancer (Jatoi et al., 2007). In another trial, 32 patients with high-grade prostatic intraepithelial neoplasia were given a lycopene-enriched diet (20–25 mg/day) for 6 months; however, no meaningful effect was observed in terms of lycopene’s effects on cancer development or PSA levels in these individuals (Mariani et al., 2014). In phase II research, Zhuang et al. have studied the clinical efficacy and safety profile of docetaxel with lycopene in CRPC patients and revealed that the combination of docetaxel and lycopene resulted in enhanced PSA response rate and tolerability (Zhuang et al., 2021).

Quercetin. Quercetin, a flavonoid found in fruits and vegetables, has been shown to have anti-inflammatory, antioxidant, and cancer-fighting properties. The activity of promoters of two major genes implicated in PCa pathogenesis, i.e., AR and PSA, is inhibited by quercetin (Ghafouri-Fard et al., 2021). By suppressing the main survival protein Akt, quercetin has also been shown to promote the apoptosis of PCa dose-dependently (Ghafouri-Fard et al., 2021). On PC-3 cells (model cells of CRPC), quercetin and paclitaxel coadministration significantly reduced cell proliferation, increased apoptosis, triggered cell cycle arrest at the G2/M stage, activated endoplasmic reticulum stress, and enhanced reactive oxygen species production (Zhang X. et al., 2020). Henning et al. have conducted a prospective randomized, parallel design, placebo-controlled trial in which 31 men with PCa were given either 1 g of green tea extract containing 830 mg of green tea polyphenols with 800 mg of quercetin or placebo for 4 weeks before prostatectomy (Henning et al., 2020). Following the coadministration of green tea extract and quercetin, they have found a significant rise in quercetin concentrations in plasma, urine, and prostate tissue. Furthermore, this regimen decreased epicatechin gallate levels in the urine. In prostate tissue or RBCs, no significant change in the concentration of green tea polyphenols or methylation activity across the groups was observed and there was no evidence of liver injury (Henning et al., 2020).

Gossypol. (-)-Gossypol, a polyphenolic chemical found in cottonseed, improves radiation therapy response and shrinks human PCa tumors (Xu et al., 2005). (-)-Gossypol induced apoptosis in DU-145 cells by downregulating Bcl-2 and Bcl-xL and increasing Bax at the mRNA and protein levels. It also enhances PARP cleavage and activates caspase-3, -8, and -9 (Huang et al., 2006). In PCa cells and prostate tumor-initiating cells, gossypol activates p53 and induces apoptosis (Volate et al., 2010). AT-101 (R-(-)-gossypol acetic acid; Ascenta Therapeutics, Inc.), a derivative of gossypol, exhibited anticancer activity in various tumor models. Liu et al. have conducted a phase I/II study of AT-101 in 23 patients with CRPC and investigated that AT-101 was well tolerated when given at a dose of 20 mg/day for 28 days (Liu et al., 2009).

(-)-Epigallocatechin-3-gallate (EGCG). (-)-Epigallocatechin-3-gallate (EGCG), biologically active catechin of green tea, has been evaluated for its chemopreventive activity against CRPC using in vitro and in vivo animal studies (Ju et al., 2005; Thangapazham et al., 2007; Rahmani et al., 2015). Bettuzzi et al. have explored cancer-preventive effects of green tea catechins (GTCs) in volunteers with high-grade prostatic intraepithelial neoplasia (HGPIN). The volunteers were given 200 mg of GTC three times daily for a total of 600 mg/d and followed up after 1 year. Only one instance of PCa in the treatment group (incidence 3%) and nine cases of PCa (incidence 30%) in the placebo group were observed (Bettuzzi et al., 2006). A decrease in PSA levels, although not significant, and a significant decrease in International Prostate Symptom Score were observed in the GTC group. Furthermore, during a 2-year follow-up, two of the nine placebo males and one of the 13 GTC patients were diagnosed with PCa, demonstrating an 80% reduction in PCa diagnosis in patients with HGPIN (Brausi et al., 2008). Polyphenon E (PolyE), a mix of GTCs, containing 400 mg of EGCG, was given daily for 1 year to men with HGPIN in a placebo-controlled, randomized clinical trial (Kumar NB. et al., 2015). A decrease in serum PSA levels and ASAP in the PolyE group was observed. In another study, males with PCa were given 1.3 g of PolyE containing 800 mg of EGCG daily (McLarty et al., 2009). A significant reduction in PSA, HGF, and VEGF serum levels was observed at the time of prostatectomy (after 3–6 weeks). Moreover, supplementation with PolyE containing 800 mg of EGCG for 3–6 weeks resulted in a beneficial but nonsignificant reduction in serum PSA in a similar clinical study (Nguyen et al., 2012). Contrary to the above observations, minimal antineoplastic action was identified after daily dosages of EGCG were given to 42 patients with androgen-independent PCa in phase II clinical study (Jatoi et al., 2003).

Curcumin. Curcumin, diferuloylmethane, inhibits PCa proliferation and metastatic development by downregulating androgen receptor and epidermal growth factor receptors and causing cell cycle arrest (Teiten et al., 2010). Twenty-six patients with advanced CRPC and elevated PSA were given docetaxel/prednisone in usual settings for six cycles, along with curcumin (6,000 mg per os each day; day −4 to day +2 of docetaxel) (Mahammedi et al., 2016). This study demonstrates that curcumin has a high response rate, good tolerability, and patient acceptability, justifying the need for a randomized trial. An RCT was conducted on 64 eligible patients with PCa to assess the beneficial role of nanocurcumin in preventing and/or mitigating radiation-induced proctitis in PCa patients undergoing RT (Saadipoor et al., 2019). 33 patients received nanocurcumin (120 mg/day) 3 days before and during the RT course. Radiation-induced proctitis occurred in 18/31 (58.1%) of placebo-treated patients compared to 15/33 (45.5%) of nanocurcumin-treated patients (Saadipoor et al., 2019). The role of anticancer effects of curcumin in patients with PCa that undergo intermittent androgen deprivation (IAD) treatment has been studied. A randomized, double-blind, placebo-controlled trial was performed on 97 patients with PCa (49 patients took oral curcumin (1440 mg/day) and 48 received placebo for 6 months) who received IAD treatment (Choi et al., 2019). The results have demonstrated that oral administration of curcumin for 6 months can lower PSA levels significantly in patients compared to those in the placebo group. Curcumin (total 3 g/day), a radiosensitizing and radioprotective agent, showed significant improvement of antioxidant status in patients with PCa who received radiotherapy (Hejazi et al., 2016). Another clinical study has been conducted to examine the effect of curcumin supplements and isoflavones on serum PSA levels (Ide et al., 2010). The isoflavones and curcumin were administered orally to patients who had prostate biopsy due to elevated PSA levels for 6 months, and a significant decrease of serum PSA level was observed. Two clinical studies on the effect of adjuvant use of curcumin after prostatectomy on improving recurrence-free survival in PCa patients (clinicaltrials.gov; NCT02064673) and reducing the risk of PCa progression in low-risk men (clinicaltrials.gov; NCT03769766) are undergoing.