2.1

Vitamin C

Vitamin C (ascorbate or ascorbic acid) is a water-soluble vitamin that is an essential nutrient for humans. Citrus fruits, berries, tomatoes, potatoes, and leafy greens are rich reservoirs of vitamin C [ ]. Vitamin C has shown promise in preclinical and small clinical trials across different cancers, including ovarian and pancreatic cancers [ ].

The function of vitamin C varies based on the dosage and mode of administration. At low doses, it serves as an antioxidant, while at high doses, it functions as a prooxidant [ , ]. Pharmacologic concentrations of vitamin C, which can only be achieved through intravenous (IV) administration rather than oral dosing, have been shown to be selectively toxic to cancer cells. The predominant mechanism through which pharmacologic vitamin C exerts its anticancer effect is via the generation of extracellular hydrogen peroxide [ , ]. These reactive oxygen species (ROS) diffuse intracellularly and induce oxidative stress in cancer cells through their downstream effects, including DNA and mitochondrial damage and apoptotic pathway stimulation [ ].

Prospective clinical trials investigating the use of vitamin C in the treatment of PCa are limited, and thus far none have demonstrated efficacy. A single-arm, phase II study reported that high-dose IV vitamin C (60g) given once weekly for 12 weeks failed to produce a PSA50 response rate (≥50% decline in PSA level from baseline) or disease remission in patients with chemotherapy-naive mCRPC [ ]. Similarly, a recent randomized, placebo-controlled, phase II trial found that high-dose IV vitamin C combined with docetaxel did not improve the PSA response rate, progression free survival, or overall survival, or mitigate docetaxel toxicity in patients with mCRPC [ ]. An ongoing phase II trial is investigating the combination of the PARP inhibitor olaparib and IV vitamin C in patients with mCRPC ( Table 1 ) [ ].

2.2

Vitamin D

The fat-soluble vitamin D3 (cholecalciferol) is synthesized in the human skin from 7-dehydrocholesterol upon exposure to sunlight or obtained from dietary sources such as fatty fish and fish oils. Vitamin D can also be ingested in the form of vitamin D2 (ergocalciferol) from plant-based sources. Regardless of its origin, vitamin D undergoes two hydroxylation reactions in the body to be converted into its biologically active form, 1,25(OH) ₂ vitamin D, also known as calcitriol [ ].

The antitumor effects of vitamin D are thought to be mediated in part through its interaction with the vitamin D receptor, which is present on human PCa cells [ ]. Upon binding to its receptor, calcitriol blocks G1 to S cell cycle phase transition, increases the levels of cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p21Waf1/Cip1, decreases CDK2 activity, decreases phosphorylation of the retinoblastoma (Rb) protein, and represses E2F transcriptional activity in LNCaP cells [ , ]. Calcitriol reduces the angiogenic signaling molecule, angiopoietin-2, decreases the levels of anti-apoptotic proteins like Bcl-2 and Bcl-xL, and stimulates the mitochondrial release of cytochrome c [ , ]. Calcitriol was found to augment the efficacy of various cytotoxic chemotherapy agents in multiple preclinical tumor models [ ].

Evidence suggests that sun exposure reduces the risk of PCa [ ], and low levels of vitamin D increase the risk [ ]. A study by Zheng et al.[ ] showed that vitamin D deficiency promotes PCa growth in bone by altering the bone microenvironment. Numerous clinical trials studying the potential role of vitamin D in the treatment of PCa have yielded conflicting results ( Table 2 ) [ ]. In the context of localized PCa or biochemical recurrence, vitamin D shows promising therapeutic potential, although clinical trials in this area are still limited [ , , , ]. Further research is needed to conclusively establish its beneficial effects in this space. Vitamin D has been extensively studied in the mCRPC setting, but it has not demonstrated efficacy, whether used alone, in combination with chemotherapy agents, or with dexamethasone [ , , , , , ]. Consequently, its use is not supported as treatment in the mCRPC space.

However, patients with PCa metastatic to the bone should be monitored for vitamin D levels, with supplementation provided when deficiencies are detected in order to prevent bone-related complications. It is important to keep vitamin D levels in the normal range, particularly in those undergoing androgen-deprivation therapy (ADT), which can cause loss of bone mineral density (BMD) and increased risk of fracture [ ]. A study showed that ADT-induced BMD loss was greatest in the lumbar spine within the first year of use. However, vitamin D supplementation was associated with improved BMD in the lumbar spine during this first year [ ]. According to the National Comprehensive Cancer Network (NCCN) guidelines, all patients receiving ADT should receive 1000–1200mg of calcium daily from food or supplements and maintain serum vitamin D3 levels of 30 to 50 ng/mL [ ]. An ongoing trial is evaluating the use of high-dose vitamin D supplementation for ADT-induced bone loss in patients with early-stage PCa ( Table 1 ). In a 2024 phase II study, high-dose vitamin D (50,000 IU/week) significantly reduced BMD loss in the hip and femoral neck, particularly for patients with low vitamin D baseline levels [ ]. Vitamin D may also improve pain, muscle strength, and quality of life in patients with mCRPC [ ]. Patients with mCRPC and bone metastases are recommended to receive antiresorptive medications, such as denosumab or zoledronic acid, to prevent disease-related skeletal complications [ ]. In these patients, maintaining normal serum vitamin D levels is particularly important, as there is an increased risk of hypocalcemia with these medications, especially in cases of vitamin D deficiency.

2.3

Vitamin E

Vitamin E is a fat-soluble antioxidant that can be divided into two major groups, tocopherols and tocotrienols, with each group consisting of four isomers: alpha, beta, gamma, and delta. Vitamin E is found in plant-based oils, nuts, and seeds, with wheat germ oil being the richest source of tocopherols, specifically α and β. Significant amounts of vitamin E can also be found in fruits and vegetables, including blackberries, avocado, broccoli, and asparagus [ ].

Tocotrienols, particularly the gamma and delta isoforms, have been demonstrated to be more effective than tocopherols in inhibiting PCa cell growth in androgen-independent PC-3 cells [ ]. Gamma-tocotrienol (γ-T3) induces PCa cell apoptosis through the suppression of NF-kB activity, epidermal growth factor receptor (EGFR) expression, and Id1 and Id3 expression [ ]. γ-T3 promotes PCa cell apoptosis through the activation of the JNK-signaling pathway and inhibits PCa cell invasion through increased expression of E-cadherin and γ-catenin [ ]. Since docetaxel induces apoptosis under hypoxic conditions by activating the JNK2/PHD1 signaling pathway [ ], the addition of γ-T3 to docetaxel enhances its effect in vitro and in vivo, suggesting a synergistic effect against PCa cells [ , ]. A tocotrienol-rich fraction extracted from palm oil selectively induces a G0/G1 cell cycle arrest and accelerates apoptotic events in PCa cells [ ]. γ-T3 downregulates the pro-angiogenic factor angiopoietin-1 (Ang-1) expression suppressing the Ang-1/Tie-2 signaling pathway in PCa cells [ ].

While the effect of vitamin E on PCa risk has been well studied, with the physicians health study reporting no risk reduction [ ] and the SELECT trial reporting increased risk [ ], its role in the treatment of PCa has rarely been studied in clinical trials. A pilot phase 0 trial determined that 2-week supplementation with high-dose γ-tocopherol-rich vitamin E increased the prostate levels of γ- and δ-tocopherols but had no significant effect on PSA reduction in patients with PCa undergoing radical prostatectomy [ ]. A phase I/IIa dose-escalation study was conducted to evaluate the effects of oral APC-100 (2,2,5,7,8-pentamethyl-6-chromanol), the antioxidant component of α-tocopherol, in patients with CRPC. APC-100 exhibits a dual mechanism of action, functioning both as a potent antioxidant and as an antiandrogen, suggesting its potential efficacy in conditions such as PCa, where oxidative stress and androgens are key factors. The study found that while APC-100 was well tolerated, with PSA stabilization occurring in 25% of patients, the maximum feasibility of the drug was reached with no detectable drug in the plasma [ ].

It will be interesting to evaluate the effects of APC-100 on PCa, if it is reformulated to allow for higher dose escalation. Preclinical studies demonstrate potential synergy between docetaxel and vitamin E through different mechanisms [ , , ]. The addition of γ-T3 and α-tocopherol ether acetate (α-TEA) to docetaxel showed improved effectiveness in reducing cell viability in resistant cells and decreased the amount of docetaxel required [ ]. The combination of γ-T3 and docetaxel lead to a synergistic effect on docetaxel-induced apoptosis [ ]. Well-designed clinical trials are needed to evaluate and validate these findings in patients with PCa. However, based on the current evidence, their implementation in clinical practice cannot yet be recommended.

2.4

Selenium

Selenium is an essential trace element that exists naturally in organic and inorganic forms. The main forms of organic selenium include selenomethionine (SeMet), selenocysteine (SeCys), and methylselenocysteine (MSeC). Inorganic selenium (selenite and selenate) requires conversion into organic forms within the body for utilization. Humans acquire selenium through dietary sources, supplements, and drinking water. Dietary intake of selenium comes from both plant-based foods, such as cereals (the primary source), nuts, vegetables, and fruits, and animal-based foods, including meat, dairy products, fish, seafood, and milk. Selenium can be found in drinking water, primarily as selenate and selenite [ ].

Selenium downregulates androgen receptor (AR) signaling and PSA expression in PCa cells [ ]. In LNCaP cells, selenium induces G1 cell cycle arrest and the upregulation of CDK inhibitors p27Kip1 and p21Cip1 [ ]. Methylseleninic acid (MSeA), a selenium metabolite, reduces hypoxia-inducible factor-1α (HIF-1α) expression and its activity along with its downstream targets, VEGF and GLUT1 [ ]. Selenite induces apoptosis in LNCaP cells, marked by an increase in superoxide production, decrease in mitochondrial membrane potential, release of cytochrome c, and activation of caspases 9 and 3 [ ]. Selenium triggers rapid transcriptional activation of p53, with upregulation of the expression of p53-target genes, such as p21, BAX, and DR5, which plays a causal role in selenium-induced apoptosis [ ]. MSeC downregulates Bcl-2 and upregulates BAD expression in DU145 cells, facilitating apoptosis [ ].

Selenium has been extensively studied for its potential role in PCa chemoprevention, but the results have been largely negative [ , ]. In fact, administering selenium at high doses may increase the risk of aggressive PCa in individuals with certain genetic factors such as the valine (V)/alanine(A) and VV- SOD2 genotype, which are present in 75% of men [ , ]. SOD2 encodes manganese superoxide dismutase (MnSOD), which is the primary mitochondrial enzyme that protects cells from oxidative stress. The AA genotype of SOD2 produces a variant of MnSOD that enables more efficient mitochondrial import and is more active than other genotypes. Among men with the AA genotype, those in the highest quartile of selenium had reduced risk of aggressive prostate cancer [ , ].

The evidence supporting the use of selenium in PCa treatment is limited. In a phase II trial, men with localized, nonmetastatic PCa under active surveillance were administered either 0 µg, 200 µg, or 800 µg of selenium in the form of selenized yeast. Although the trial showed no significant overall impact on PSA velocity, it did find that PSA velocity increased in men who already had high baseline plasma selenium levels [ ]. Furthermore, research by Kenfield et al. [ ] indicated that men with nonmetastatic PCa who supplemented with selenium after diagnosis faced an increased risk of PCa mortality.

Based on these findings, the use of selenium in PCa treatment is not recommended and should be approached with caution due to the potential harmful effects at high doses [ ]. In the SELECT trial, there was a nonsignificant increase risk of type 2 diabetes mellitus in the selenium arm (HR = 1.07) [ ], but in the updated results the HR moved closer to 1 (HR = 1.04) [ ]. However, the potential risk of diabetes with selenium supplementation cannot be excluded, as studies have shown mixed results [ , ].

2.5

Zinc

The primary dietary sources of zinc include red meat, seafood, poultry, grains, and legumes. In the United States, there is inadequate intake of zinc in 20%–25% of adults ages 60 or older [ ]. Interestingly, the normal prostate tissue contains the highest level of zinc compared to any other soft tissue in the human body, a level that significantly declines during the development of PCa [ , ].

Preclinical studies have suggested that zinc supplementation could have therapeutic potential in PCa by restoring normal zinc levels in PCa cells. Physiological levels of extracellular zinc inhibit the growth of LNCaP and PC-3 cells, which is dependent on the ability of PCa cells to accumulate high levels of intracellular zinc [ ]. Physiological levels of zinc induce apoptosis in PCa cells through multiple mechanisms including zinc’s direct effect on BAX-associated pore formation in the mitochondria leading to the release of cytochrome c, which initiates the caspase cascade [ ]. Zinc induces a G2/M cell cycle arrest that is accompanied by the upregulation of p21Waf1/Cip1/Sdi1 mRNA levels [ ].

Findings from the Health Professionals Follow-up Study indicated that long-term, high-dose zinc supplementation (more than 75 mg/day over 15 years) may increase the risk of developing aggressive PCa [ ]. In contrast, the same study found that low-dose zinc supplementation (1–24 mg/day) in patients with nonmetastatic PCa was associated with a lower risk of lethal PCa and all-cause mortality [ ]. Supporting this, a study of dietary zinc intake in a Swedish cohort of PCa patients revealed that higher zinc intake from dietary sources (9–20.1 mg/day) was associated with lower PCa-specific mortality, particularly in patients with localized disease [ ].

Given the association between high-dose, long-term zinc supplementation and the increased risk of developing clinically significant PCa, caution is warranted when considering excessive zinc intake in healthy adult males. However, zinc supplementation as a treatment for PCa remains intriguing and warrants further clinical investigation. In addition, the impaired ability of PCa cells to accumulate and secrete zinc, as indicated by urinary zinc levels, may hold promise as a biomarker for early disease detection [ ].

3.1

Curcumin

Curcumin (diferuloylmethane) is the principal bioactive polyphenol of turmeric, which is derived from Curcuma longa rhizomes. Turmeric is widely used as a spice and is the source of curry, with its distinctive yellow color and flavor. It is also used as a coloring agent in butter, cheese, and other food items [ ].

Curcumin treatment leads to the reduction of intracellular testosterone levels in the prostate, thereby preventing AR activation [ ], decreases AR expression at the mRNA and protein level [ ], and downregulates NKX3.1 gene expression [ ]. Curcumin decreases cell proliferation, increases the extent of apoptosis, and inhibits angiogenesis in PCa cells [ ]. Furthermore, curcumin selectively induces apoptosis in PCa cells, which correlates with the downregulation of antiapoptotic proteins, Bcl-2 and Bcl-xL, and activation of caspases 3 and 8 [ ]. The PI3K/AKT signaling pathway is inhibited by curcumin, enhancing apoptosis in PCa cells [ ]. Curcumin also inhibits cell proliferation and tumor progression by inducing the degradation of β-catenin through the regulation of downstream molecules of the Wnt/β-catenin signaling pathway. Since β-catenin is a coactivator of AR transcription, this is an alternative pathway through which curcumin can downregulate AR expression [ ].

Curcumin’s therapeutic efficacy has been studied in numerous clinical trials for a wide range of diseases. A randomized, placebo-controlled trial in patients with PCa undergoing intermittent ADT studied the effect of oral curcumin for 6 months beginning from ADT withdrawal. The overall off-treatment duration of intermittent ADT was not significantly affected, but there were significantly lower PSA progression rates in the curcumin group [ ]. A randomized controlled trial assessed the radio-sensitizing and radio-protective effects of oral curcumin in patients with PCa undergoing radiotherapy. The results showed a reduction in PSA levels to below 0.2ng/ml in both the curcumin and control groups, with no significant differences observed between them [ ]. A single-arm phase II study investigating the combination of docetaxel and oral curcumin in patients with progressing, chemotherapy-naïve mCRPC demonstrated a higher response rate compared to historical controls treated with docetaxel alone. The combination was well tolerated, with no adverse events attributed to curcumin [ ]. A randomized, controlled trial is needed to definitively establish curcumin’s contribution to the efficacy of the combination.

Three ongoing trials are evaluating the use of curcumin in managing patients with early-stage PCa ( Table 1 ). Turmeric has been associated with liver injury and must be used with caution, especially with the use of black pepper and in patients carrying the HLA-B*35:01 allele, which are thought to increase the risk of turmeric associated liver injury [ ].

3.2

Lycopene

Lycopene is a powerful lipid-soluble, red pigment antioxidant that corresponds to the class of phytochemicals called carotenoids. It is found in high concentrations in tomatoes, tomato-based products, red and pink grapefruits, papaya, pink guava, and watermelon. The bioavailability of lycopene increases after thermal treatment and when consumed with fat or oils. Tissue distribution of lycopene varies, with the highest accumulation in the prostate, testes, adrenal glands, and liver [ ].

Lycopene protects against oxidative damage by increasing the expression of detoxification proteins, including epoxide hydrolase-1, superoxide dismutase-1, catalase, and transferrin [ ]. It increases phase II protective enzymes and downregulates proteins involved in ROS generation [ ]. Lycopene protects against DNA-based oxidative damage, which leads to a decrease in 8-hydroxy-2′deoxyguanosine (8-OHdG) levels, a specific marker for oxidative DNA damage [ ]. At the same time, lycopene at higher than physiological concentrations may result in pro-oxidative effects [ , ]. Lycopene blocks the G1/S phase of the cell cycle with a decrease in cyclin D1 and an increase in the CDK inhibitors: p53, p21Waf1/Cip1, and p27 [ ]. Lycopene increases apoptosis, inhibits cell viability, upregulates p53 and BAX transcript expression, and downregulates Bcl-2 expression in PCa cells [ ]. In LNCaP cells, lycopene decreases the expression of Bcl-2 and Bcl-xL and increases that of BAX [ ]. In PC3 cells, the antiproliferative effect of lycopene results in upregulation of IGFBP-3 expression and downregulation of IGF-1-induced IGF-1R expression [ ]. Lycopene inhibits cell proliferation and induces apoptosis in PC3 cells via the upregulation of miR-let-7f-1 and downregulation of AKT2 expression [ ]. Lycopene inhibits AR gene element expression, leading to the reduction of PSA velocity [ ]. It exhibits antiangiogenic activity through the decrease in VEGF levels [ ]. Lycopene decreases α2β1, αvβ3, and αvβ5 integrins, which may affect PCa cell invasion and migration [ ].

Several studies investigating the relationship between lycopene and PCa risk have yielded mixed results. While most studies demonstrated that higher dietary and circulating lycopene concentrations are associated with lower PCa risk, others reported no effect [ , ]. Similarly, there have been mixed results in the use of lycopene in PCa treatment. For instance, a 3-week lycopene-rich tomato intervention in patients with localized PCa prior to prostatectomy or radiotherapy showed no significant differences in PSA levels between the treatment and control groups. However, a post-hoc analysis revealed that patients with intermediate-risk PCa experienced a significant reduction in PSA levels following lycopene intervention compared to the control group. This suggests that the effect of lycopene may vary depending on the aggressiveness of the disease [ ]. A phase II trial investigating the effect of lycopene on patients with localized PCa prior to radical prostatectomy suggested that lycopene supplementation can decrease PCa growth [ ]. Two trials, one in patients with localized PCa and the other in those with biochemically recurrent PCa (BCRPC), investigated escalating doses of lycopene supplementation on PSA response. No PSA response was observed, despite an increase in plasma lycopene levels from baseline [ , ]. Similarly, a trial with patients with BCRPC receiving lycopene daily yielded no PSA response, though there was a stabilization in PSA levels for a minimum of three months in 95% of patients [ ]. Among patients with progressive mCRPC receiving daily lycopene monotherapy for three months, 35% had a PSA response and 50% had stable PSA with improved ECOG performance status, reduced bone pain, and less urinary tract symptoms [ ]. Similar results were obtained in a study comparing orchidectomy versus orchidectomy-lycopene combination in the treatment of metastatic hormone-sensitive PCa. The combination group resulted in a more durable decrease in PSA levels, reduced bone pain, improved urinary tract symptoms, and longer overall survival compared to the orchidectomy group [ ]. A PSA50 response was not achieved in a phase II pilot study that enrolled patients with progressive CRPC receiving daily lycopene supplementation for 6 months [ ]. A phase II study that examined the combination of docetaxel and lycopene in chemotherapy and biological therapy-naive patients with mCRPC had a PSA response rate of 76.9% and a median overall survival of 35.1 months, efficacy that compared favorably with previously reported studies. However, the study was limited by a small sample size and lack of a control group [ ].

Lycopene has shown promising therapeutic effects in treating PCa and in alleviating cancer-related symptoms. However, its efficacy needs to be validated in larger, well-controlled clinical trials.

3.3

Plumbagin

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naturally occurring naphthoquinone derived from the roots of the medicinal plant Plumbago zeylanica L . (chitrak). It is also found in Juglans regia (English walnut), Juglans cinerea (butternut and white walnut), and Juglans nigra (blacknut) [ ].

Plumbagin induces apoptosis [ ], inhibits angiogenesis [ ], and decreases AR levels in PCa cells [ ]. It has been shown to significantly enhance the efficacy of ADT and CYP17A1 inhibitors in PCa, leading to increased survival in mice compared to ADT alone. However, when combined with AR antagonists such as bicalutamide and enzalutamide, no additional benefit was observed [ ].

The first-in-human study of PCUR-101, a synthetic form of plumbagin, was conducted as a phase I dose-escalation trial in patients with mCRPC. Patients received increasing doses of oral PCUR-101 in addition to ADT. Due to limited activity, further clinical development of this compound was not pursued [ ].

3.4

Green tea polyphenols (catechins)

Green tea is produced by steaming and drying the fresh leaves from the Camellia sinensis plant. The main antioxidant agents in green tea are catechins, which are polyphenols responsible for the distinctive bitter taste. The four major catechins present in green tea leaves are epigallocatechin-3-gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), and epicatechin (EC). Among these, EGCG is the most studied and most potent bioactive compound that targets multiple molecular pathways involved in PCa development [ ].

EGCG suppresses tumor growth and cell proliferation of both androgen-sensitive and androgen-independent PCa cells in vitro and in vivo [ ]. It decreases the levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt, and increases extracellular signal-regulated kinase (Erk) 1/2 [ ]. EGCG reduces NF-kB transcriptional activity, leading to the decrease in the antiapoptotic protein Bcl-2 levels. It also stabilizes p53 increasing its transcriptional activity, which leads to activation of its downstream targets p21/Waf1 and BAX. The change in the BAX/Bcl-2 ratio favors apoptosis [ ]. EGCG treatment in PCa cells, with or without TP53 mutations, results in dose- and time-dependent upregulation of CDK inhibitors, specifically p21/Waf1, p27/Kip1, p16/INK4a, and p18/INK4c, and downregulation of cyclin D1, cyclin E, CDK2, CDK4, and CDK6, resulting in G0/G1 phase cell cycle arrest [ ]. EGCG increases binding of cyclin D1 toward p21/Waf1 and p27/Kip1 and decreases binding of cyclin E toward CDK2 [ ]. EGCG represses the transcription of the AR gene and downregulates the IGF-1 signaling pathway, thereby slowing the progression of PCa [ , ].

Clinical trials examining the use of green tea or its extracts as a treatment or adjunct therapy for PCa have shown mixed results. Administration of polyphenon E (800mg EGCG) for three to six weeks in patients with PCa prior to prostatectomy showed low prostate tissue bioavailability. There was a decrease in the levels of PSA and IGF-1 and in markers of oxidative DNA damage, but none were statistically significant [ ]. In an open-label, phase II trial, patients with PCa were randomized to six cups daily of brewed green tea, black tea, or water before prostatectomy, which led to a small but significant decrease in PSA levels in the green tea group [ ]. In another phase II trial, patients with progressive CRPC consumed 6 grams of green tea daily for 4 months. Only 1 of 42 patients achieved a PSA50 response, but it was not sustained beyond two months [ ]. A small, single-arm study investigating 250mg of green tea capsules twice daily for up to 5 months in patients with CRPC resulted in no PSA50 responses. Of 19 patients enrolled, only 15 completed the minimum two months of therapy and all were found to have progressive disease within 1 to 5 months of therapy [ ].

Green tea, particularly its catechins such as EGCG, shows potential for PCa prevention and treatment due to its antioxidant, anti-inflammatory, and anticancer properties. However, evidence remains inconclusive, and more research is needed to clarify its benefits and risks. While generally safe in moderate amounts, high doses of green tea extract have been linked to liver toxicity in some cases [ , ]. Therefore, its use as a therapeutic agent should be approached with caution and under medical supervision.

3.5

Soy isoflavones

The phytoestrogen isoflavone, a diphenolic compound, belongs to the flavonoid subgroup. The main sources of isoflavones are legumes from the Fabaceae family, with soybeans being the most common dietary source of daidzein, genistein, and glycitein [ ]. Daidzein undergoes biotransformation by the gut microbiota into equol, which has greater stability, bioavailability, binding affinity to estrogen receptors, and antioxidant activity [ ]. Other sources of isoflavones include red clover (Trifolium pratense) and kudzu root (Radix Pueraria) [ ].

Soy isoflavones share structural similarities with 17β-estradiol, enabling them to bind to both estrogen receptors alpha (ERα) and beta (ERβ). Genistein, a key isoflavone, has an affinity for ERβ that is 20–30 times higher than for ERα [ , ]. The distribution of these receptors varies across tissues; ERα is more abundant in the uterus and mammary glands, while ERβ is more prevalent in the ovary and prostate tissues [ , ]. Physiological concentrations of genistein downregulate AR mRNA and protein expression, and thereby PSA secretion, through ER-β activation [ ]. Genistein inhibits PCa cell growth in culture independent of androgen sensitivity [ ]. In PCa cells, genistein induces a G2/M cell cycle arrest and apoptosis, with downregulation of cyclin B and upregulation of p21/Waf1 growth‐inhibitory protein [ ]. In LNCaP cells, physiologic concentrations of genistein induce a G1 cell cycle arrest and upregulation of p27/Kip1 and p21/Waf1 mRNA and protein expression, leading to potent antiproliferative effects [ ]. Genistein also downregulates PSA mRNA expression [ ]. It inhibits IGF-1-stimulated cell growth and phosphorylation of IGF-1R and the phosphorylation of its downstream targets Src, Akt, and glycogen synthase kinase-3β (GSk-3β) [ ]. Isoflavones inhibit Akt and FOXO3a phosphorylation, downregulate Src signaling, and upregulate GSk-3β expression, which leads to down-regulation of AR and its target gene PSA . This regulation of the Akt/FOXO3a/GSK-3β/AR signaling network leads to the inhibition of cell proliferation and induction of apoptosis [ ]. Genistein inhibits prostate tumor angiogenesis through suppression of VEGF expression [ ].

PCa incidence is significantly higher in Western populations compared to Asian populations, where soy foods rich in isoflavones, such as genistein and daidzein, are widely consumed. Japanese men, for example, have serum isoflavone levels that are 10–100 times higher than those of European men [ ]. A systematic review and meta-analysis by Applegate et al. concluded that higher soy consumption significantly reduces the risk of PCa [ ]. Given this potential benefit, soy is being explored for its therapeutic potential in PCa treatment. A study with oral genistein-rich extract as a sole treatment for six months did not achieve a PSA50 response in 51 of 52 patients with PCa experiencing biochemical failure. However, a stabilization or decline in PSA levels occurred in 8 of 13 patients in the active surveillance group [ ]. A phase II trial investigated the supplementation of 141mg isoflavone daily for 12 months in patients with BCRPC and found a decline of the PSA slope [ ]. Another phase II trial in patients with localized PCa on 30mg of synthetic genistein daily for 3–6 weeks prior to prostatectomy showed a 7.8% PSA decrease in the genistein group and 4.4% PSA increase in the placebo group ( P = 0.051) [ ]. In a double-blind, randomized trial in patients with localized PCa on active surveillance, daily consumption of an aglycone isoflavone supplement (450mg genistein, 300mg daidzein, and other isoflavones) for 6 months showed a significant increase in serum concentrations of genistein and daidzein, but no reduction in PSA levels [ ]. Patients with localized PCa receiving a short course of isoflavones prior to prostatectomy showed no significant changes in PSA compared to the control group [ , ]. Similarly, patients with BCRPC after prostatectomy supplemented with 23–26mg of genistein and 40–43mg of total isoflavones for six to eight months had no difference in PSA doubling time (PSADT) compared to the placebo group [ ]. A pilot study investigating the administration of 200mg soy isoflavone daily for 6 months in patients with localized PCa receiving external beam radiation therapy showed a decrease in radiation-induced adverse effects on bladder, bowel, and sexual function at 3 and 6 months in the soy isoflavone group compared to the placebo group [ ]. Similarly, another pilot study evaluating the effects of 20g soy protein containing 160mg total isoflavones for 12 weeks on the side effects of ADT in patients with PCa showed no significant improvement in vasomotor symptoms, cognition, or other quality-of-life measures in the isoflavone group compared to the placebo group [ ].

Soy isoflavones do not show a promising therapeutic effect on PSA reduction in patients with BCRPC or localized PCa. However, enhancing the biological activity and potential efficacy of soy isoflavones could be achieved through optimizing their biotransformation into equol by the gut microbiota. Factors such as dietary habits, including higher soy consumption in Asian and vegetarian diets [ ], as well as prebiotics and probiotics [ , ], influence gut microbiota composition and equol production. In addition, given the antimetastatic properties of soy isoflavones and the lack of available clinical trials in advanced PCa, clinical trials in this space should be considered [ ].

3.6

Pomegranate

Pomegranate (Punica granatum) is a significant source of two types of polyphenolic compounds: anthocyanins and hydrolyzable tannins. Anthocyanins, including delphinidin, cyanidin, and pelargonidin, are responsible for the red color of the fruit and juice. Hydrolyzable tannins, including punicalin, pedunculagin, punicalagin, gallagic and ellagic acid esters of glucose, account for 92% of the fruit’s antioxidant activity. In pomegranate juice, the amount of soluble polyphenols ranges from 0.2% to 1% [ ].

In androgen-dependent and androgen-independent PCa cells, treatment with pomegranate polyphenols arrests proliferation and stimulates apoptosis through multiple mechanisms and inhibits gene expression of enzymes involved in androgen synthesis and AR signaling [ ]. Pomegranate extract upregulates p21/Waf1 and p27/Kip1 expression, leading to G1 phase cell cycle arrest and apoptosis [ ]. It also upregulates BAX and downregulates Bcl-2 expression, altering the BAX to Bcl-2 ratio to favor apoptosis [ ]. Pomegranate extract inhibits the IGF-1/Akt/mTOR pathway, leading to inhibition of cell survival and growth [ ]. In vivo, oral pomegranate extract significantly reduces tumor growth, with an associated significant decrease in PSA levels in athymic nude mice implanted with androgen-sensitive CWR22Rv1 cells [ ]. It inhibits NF-κB activity in PCa models both in vitro and in vivo [ ]. In an LAPC4 murine xenograft model, pomegranate extract delayed the development of androgen independence by inhibiting proliferation and inducing apoptosis [ ]. The TRAMP mice supplemented with pomegranate extract exhibited significant inhibition of PCa and metastasis development as well as a doubling in overall survival time [ ].

A single-arm, phase II trial in patients with BCRPC assessed the effects of daily consumption of 8 ounces of pomegranate juice until disease progression. The study found a significant increase in PSADT, from a baseline mean of 15 months to a mean of 60 months after treatment. Additionally, there was a 60% reduction in the median PSA slope, decreasing from 0.06 to 0.024 [ , ]. Similarly, the impact of 8 ounces of pomegranate liquid extract on PSADT was evaluated in patients with BCRPC through a double-blind, placebo-controlled trial. Although both the treatment and placebo groups showed a prolongation of PSADT, the difference was not statistically significant. However, a preplanned subset analysis, focused on patients with the manganese superoxide dismutase (MnSOD) alanine/alanine (AA) variant, revealed that those treated with pomegranate extract experienced a statistically significant increase in PSADT from 13.6 to 25.6 months, compared to an increase from 10.9 to 12.7 months in the control group [ ]. In a double-blind phase II trial, patients with BCRPC were randomized to receive either 1g or 3g of pomegranate extract (POMx) daily for up to 18 months. The overall median PSADT increased from 11.9 months at baseline to 18.5 months after treatment. No significant difference was found between the two dosage groups, with an increase in median PSADT from 11.9 to 18.8 months in the low-dose group and from 12.2 to 17.5 months in the high-dose group [ ]. To study if pomegranate juice could be used as an adjunct intervention in patients with advanced PCa, a double-blind, randomized, placebo-controlled phase IIb trial was conducted, with most patients having CRPC. The study found no significant differences in PSA levels between those receiving 500ml of pomegranate juice daily for 4 weeks and those receiving a placebo [ ]. POMx was also evaluated in the neoadjuvant setting for patients with localized PCa prior to radical prostatectomy. Patients were randomized to receive either 2 tablets of POMx, with each capsule containing 1000mg of POMx powder (including 600 mg of polyphenol from extract), or placebo daily for up to 4 weeks. The trial found a 16% reduction in prostatic 8-OHdG, a marker of oxidative stress, in the POMx group compared to the control group, although this reduction was not statistically significant [ ].

While pomegranate extract showed limited efficacy in patients with PCa, a subset of patients with the MnSOD AA genotype demonstrated promising results. Further studies are needed to validate the AA- SOD2 genotype as a genetic biomarker to predict which patients are likely to benefit from pomegranate-based supplements.

3.7

Resveratrol

Resveratrol (3,4′,5-trihydroxy-stilbene) is a plant-derived polyphenolic phytoalexin synthesized in response to environmental stressors. It is present in cis and trans stereoisomeric forms, with trans being the predominant and biologically active form. Mainly concentrated in grape skins and red wine, resveratrol can also be found in raspberries, blueberries, pines, and peanuts [ ].

Resveratrol treatment suppresses androgen-responsive genes, including PSA , human glandular kallikrein-2, AR coactivator ARA70 , and the CDK inhibitor p21 , at both protein and mRNA levels, as a result of the decrease in the AR protein levels [ ]. The impact of resveratrol on AR-dependent gene activity is concentration-dependent, with low concentrations enhancing its expression and higher concentrations repressing it [ ]. In human adrenocortical cells, resveratrol inhibits steroidogenesis by decreasing CYP17 and CYP21 enzyme expression and activity [ ]. Resveratrol inhibits transcriptional activity of ARV7, a splice isoform of AR correlated with the CRPC phenotype [ ]. Resveratrol, alone or in combination with docetaxel, upregulates p53 expression, leading to increased expression of the CDK inhibitors p21/Waf1/Cip1 and p27/Kip1 and decreased expression of the cyclin D1/CDK4 complex, therefore blocking cell cycle progression from the G1 to S phase [ ]. Cell cycle arrest at the G2/M checkpoint is prompted by resveratrol alone or with docetaxel, which is associated with the downregulation of cyclin B1 and CDK1 expression [ ]. Resveratrol promotes apoptosis through the upregulation of the pro-apoptotic proteins, including BAX, BID, and BAK, and downregulation of the anti-apoptotic proteins, including Bcl-2, Mcl-1, and Bcl-xL [ ]. Through AR inhibition, resveratrol stimulates phosphatase and tensin homolog (PTEN) expression, which negatively regulates the PI3K/AKT pathway [ ].

Clinical trials investigating the anticancer effects of resveratrol are limited. A phase I study evaluated increasing doses (500 to 4000mg) of MuscadinePlus (MPX), pulverized muscadine grape skin containing ellagic acid, quercetin, and resveratrol in patients with BCRPC. MPX prolonged PSADT by 5.3 months, but these results were not significant [ ]. This trial was followed by a phase II, randomized, placebo-controlled trial, which found that MPX did not significantly prolong PSADT compared to placebo. However, a notable exception was observed in patients with the SOD2 Ala/Ala genotype, where MPX significantly increased PSADT [ ]. To further investigate, a phase III, randomized, placebo-controlled trial assessed the efficacy of MPX in patients with BCRPC and the SOD2 Ala/Ala genotype. This study found no significant difference in PSA slope or PSADT between the MPX and placebo group [ ].

MPX treatment, which contains resveratrol, did not have a significant effect on PSA reduction in patients with BCR. It is not recommended as a treatment alternative to ADT in patients with BCR.

4.1

Omega-3 fatty acids

Omega-3 fatty acids are essential polyunsaturated fats that play a critical role in maintaining overall health. They are particularly well-known for their benefits related to heart health, brain function, and inflammation. In recent years, omega-3 fatty acids have also been studied for their potential impact on cancer, including PCa. Fish is the primary source of omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [ ].

Omega-3 fatty acids inhibit the growth and development of PCa through multiple mechanisms. DHA induces apoptosis and autophagy through mitochondrial ROS-mediated Akt-mTOR signaling in TP53 mutated PCa cells [ ]. DHA and EPA prevent the progression of PCa to an androgen-independent state, which was correlated with a decrease in AR expression and suppression of the Akt/mTOR signaling pathway [ ]. In a C3(1) Tag mouse model, a high omega-3 diet was found to slow prostate tumorigenesis by lowering testosterone and estradiol levels, resulting in a decrease in AR expression and downregulation of the expression of genes in the NF-κB and the antiapoptotic Bcl-2 pathways [ ].

Current studies investigating omega-3 fatty acids in PCa have shown mixed results. The effect of 3g/day of fish oil for three months in patients with low-risk PCa on active surveillance resulted in no change in PSA level compared to the placebo group [ ]. A study of patients with low-risk PCa who underwent first active surveillance repeat prostate biopsy concluded that high levels of long chain omega-3 fatty acids in the prostate tissue were associated with a decreased risk of high-grade PCa [ ]. A prospective dietary study was done of patients with untreated, localized PCa consuming a low-fat, fish oil-supplemented diet for three months. This resulted in a significant elevation in the omega-3/omega-6 fatty acid ratios in plasma and adipose tissue but no significant changes in PSA levels [ ]. A population-based cohort of over 500 Swedish men with localized and advanced PCa followed for 20 years post-diagnosis revealed that high marine omega-3 supplementation may improve disease-specific survival [ ]. In a randomized, placebo-controlled, phase II trial, patients with localized PCa received long-chain omega-3 fatty acid supplementation or placebo daily starting seven weeks prior to radical prostatectomy and continuing for up to one-year post-radical prostatectomy. Long-chain omega-3 fatty acid supplementation showed no improvement in overall quality of life, but it did improve urinary function [ ]. In a similarly designed study, omega-3 supplementation did not improve the psychological symptoms, including depression and anxiety, of patients with PCa who underwent a radical prostatectomy [ ]. A phase II trial investigated patients with PCa receiving either a low-fat diet with 5g/day of fish oil or a control Western diet for 4–6 weeks prior to radical prostatectomy. No significant changes in serum IGF-1 or PSA levels were found between the diets, but there was a reduction in malignant epithelial cell proliferation measured by Ki67 immunostaining [ ]. On the other hand, in a phase II trial, patients with PCa receiving 3g/day of EPA esterified in monoacylglycerides (MAG-EPA) for seven weeks prior to radical prostatectomy did not show a difference in Ki67 expression compared to the placebo group [ ]. The effect of 2.4g/day of EPA for 2 years on PSA was studied in patients with PCa postradical prostatectomy. There was no difference in PSA recurrence rates between the treatment and placebo groups [ ].

Although no therapeutic effect of short-term omega-3 supplementation in PCa was observed, long-term use may still provide benefits.

4.2

Protein intake

The relationship between protein intake and prostate cancer outcomes is a topic of ongoing research and debate. While total protein intake alone may not directly affect prostate cancer outcomes, the type of protein consumed appears to play a significant role. Studies have suggested that diets high in animal protein, particularly red and processed meats, may be linked to an increased risk of prostate cancer and its progression [ ]. This potential risk is attributed to factors such as saturated fat content, heme iron, and carcinogenic compounds produced during high-temperature cooking methods like grilling or barbecuing [ , ].

Conversely, plant-based proteins, found in foods such as legumes, nuts, seeds, and whole grains, have been associated with a reduced risk of prostate cancer progression [ ]. Dietary patterns such as the Mediterranean diet, which emphasize plant-based foods and healthy fats, have shown promise in improving prostate cancer outcomes and overall health [ , ]. Plant-based proteins provide additional health benefits as they are rich in fiber, antioxidants, and phytochemicals, which may contribute to their protective effects against cancer.

Although more research is needed to establish definitive conclusions, current evidence supports recommending dietary modifications to patients. Red and processed meats, such as beef, pork, lamb, bacon, sausages, and deli meats, should be limited to reduce potential risks. Instead, increasing the consumption of plant-based proteins like legumes, beans, lentils, nuts, seeds, and whole grains can offer protective benefits. In addition, incorporating fish rich in omega-3 fatty acids, such as salmon and mackerel, and lean poultry into the diet may serve as healthier protein sources. These dietary adjustments may help reduce the risk of prostate cancer and its progression as well as contribute to improved overall health outcomes.