Table 1.
List of phytochemicals undergone clinical trials for PCa therapy.
| Kind of supplement/Compound | Type of study | No. of patients and time period | Outcome | Reference |
|---|---|---|---|---|
| CURCUMIN | ||||
| Curcumin | A randomized, double-blind, placebo-controlled trial in patients who received intermittent androgen deprivation (IAD). | n = 97, oral Curcumin (1440 mg/day) or placebo for six months | Curcumin intake did not significantly change the overall off-treatment duration of IAD but PSA enhancement was suppressed. Curcumin was safe and well tolerated by patients. | Choi et al. (2019) |
| Curcumin | A double-blinded, randomized, placebo-controlled study in patients during radiotherapy | n = 40, Curcumin (total 3 g/day) or placebo during external-beam radiation therapy of up to 74 Gy for 3 months | Curcumin intake significantly increased total antioxidant capacity, with a reduction in SOD activity. PSA level was lowered in both the groups but nonsignificant differences in treatment outcomes between the groups. | Hejazi et al. 2016) |
| Curcumin | A pilot clinical trial in patients during radiotherapy | n = 40, 3 g/d Curcumin (6 × 500 mg capsules, n = 20), or placebo group (n = 20) during external-beam radiation therapy for 20 weeks | Curcumin intake provided radioprotection by reducing the severity of radiotherapy-related urinary symptoms. But did not reduce the intensity of bowel and other treatment related symptoms. | Hejazi et al. (2013) |
| LYCOPENE | ||||
| Fruit juice containing lycopene | In vivo double-blind placebo-controlled matched study | n = 60, a daily supplement for 28 days | Serum antioxidant, folate and, lLycopene level were increased while oxidative stress markers and homocysteine levels were decreased | Kawashima et al. (2007) |
| Lycopene tablet | A phase II randomized clinical trial before radical prostatectomy | n = 26, 15 mg Lycopene tablet twice a day for 3 weeks | Decreased PSA, IGF-1, and connexin-43 level with a reduction in chance and growth of PCa | Kucuk et al. (2001) |
| Lycopene with green tea catechins | A phase II randomized placebo-controlled trial | n = 133, daily green tea drink (3 cups, unblinded) or capsules [blinded, 600 mg flavan-3-ol ()-Epigallocatechin-3-gallate (EGCG) or placebo] and Lycopene-rich foods (unblinded) or capsules (blinded, 15 mg Lycopene or placebo) for 6 months | Reduced PCa risk. Lycopene and EGCG concentration was increased in men having an increased risk of PCa. | Lane et al. (2018) |
| Lycopene | A human intervention trial | n = 23, 40 mg Lycopene for 2 weeks | Showed cancer-preventive potential through the reduction in oxidative and other DNA damages. | Pool-Zobel et al. (1997) |
| Lycopene | An unblinded, randomized, Phase I clinical trial | n = 61, 30 mg Lycopene with a multivitamin | Increased serum level of Lycopene with reduced PSA level. | Bunker et al. (2007) |
| Lycopene | A phase II randomized trial among men with high-grade prostatic intraepithelial neoplasia (HGPIN) | n = 58, 30 mg Lycopene for 6 months | No significant change in serum PSA, IGF-1/3, MCM-2, and p27 levels. People in the Lycopene group had more extensive atrophy and less extensive HGPIN. | Gann et al. (2015) |
| Lycopene and green tea | The Pro-diet randomized controlled trial | n = 133, daily Lycopene (n = 44 assigned 15 mg capsules/day; 44 assigned a Lycopene-rich diet; 45 assigned placebo) and green tea (n = 45 assigned 600 mg/day epigallocatechin gallate; 45 assigned green tea drink; 43 assigned placebo) for 6 months | Serum Lycopene and EGCG level increased with a little reduction in serum IGF-1/2, IGFBP-2/3 level. | Biernacka et al. (2019) |
| Lycopene with tomato sauce | A randomized placebo-controlled study with a nonrandomized 5th arm study | n = 32, daily 30 mg Lycopene containing tomato sauce for 3 weeks before radical prostatectomy. | Serum and prostate Lycopene levels were increased with a concomitant decrease in PSA and Leukocyte DNA S–OH deoxyguanosine/deoxyguanosine (SOHdG) level. Reduced DNA damage with high apoptotic index in hyperplastic and neoplastic cells. | Bowen et al. (2002) |
| Lycopene and soy isoflavone | A phase II clinical trial | n = 71, 15 mg capsule of Lycopene alone or a capsule of Lycopene in combination with 40 mg of soy isoflavone twice daily for 6 months | Lycopene and combinatorial treatment with soy isoflavone did not reduce PSA level instead stabilized its level in the patient's serum. Both can delay the progression of hormone-refractory and hormone-sensitive PCabut did not have an additive effect. | Vaishampayan et al. (2007) |
| Lycopene | Phase I-II trial relapsed PCa patients | n = 36, Lycopene 15, 30, 45, 60, 90, and 120 mg/day for 1 year | Decreased serum PSA level with an increase in serum Lycopene level | Clark et al. (2006) |
| POLYPHENOLS FROM TEA | ||||
| Green tea, black tea | Randomized Phase II clinical trial | n = 113, 6 cups/day for 3–8 weeks before radical prostatectomy | Modulation of NF-κB in radical prostatectomy tissue, urinary 8- OHdG, and serum PSA levels were significantly decreased mainly in green tea, but not in the black tea group. | Henning et al. (2015) |
| Green tea | In men with clinically localized PCa | n = 17, 6 cups/day for 3–8 weeks | (−)-Epigallocatechin and (−)-Epicatechin were present in methylated form within prostatectomy tissue and this methylated EGCG may efficiently modulate its preventive effect on PCa. | Wang et al. (2010) |
| Polyphenon E (PolyE) | A placebo-controlled, randomized clinical trial in men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP) | n = 97, 400 mg EGCG for 1 year | Serum PSA level was decreased followed by accumulation of EGCG in plasma and was well tolerated in patients | Kumar et al. (2015) |
| Tea polyphenols polyphenon E (PolyE) | Short term supplementation study in PCa patients | n = 26, 800 mg EGCG, and lesser amounts of (−)-Epicatechin, (−)-Epigallocatechin, and (−)-Epicatechin-3-gallate (a total of 1.3 g of tea polyphenols) daily until radical prostatectomy | Decrease in serum PSA level, hepatocyte growth factor, and VEGF in PCa patients was observed with no increase in liver enzymes. | McLarty et al. (2009) |
| Polyphenon E | A randomized, double-blind, placebo-controlled trial in patients scheduled for radical prostatectomy. | n = 50, 800 mg EGCG or placebo daily for 3–6 weeks | Low accumulation of EGCG in the prostate tissue, favorable though insignificant changes in PSA, IGF, and oxidative DNA damage in blood leukocytes. | Nguyen et al. (2012) |
| POMEGRANATE JUICE | ||||
| Pomegranate juice | A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy | n = 46, daily 8 ounces of pomegranate 570 mg total polyphenol gallic acid equivalents for | Elongation of PSA doubling time was observed in patients without any adversity along with a reduction in cell proliferation, increase in apoptosis, serum nitric oxide and reductions in oxidative state and sensitivity to oxidation of serum lipids in vitro LNCaP cells | Pantuck et al. (2006) |
| Pomegranate juice (POMx) | A randomized, multi-center, double-blind phase II study | n = 104, daily 1 or 3 g of POMx for 18 months | Prolongation of PSA doubling time (⩾6) months without adverse side effects. | Paller et al. (2013) |
| RESVERATROL AND GRAPES | ||||
| Resveratrol | A randomized placebo-controlled clinical study | n = 66, two doses of Resveratrol 150 mg or 1000 mg Resveratrol daily for 4 months. | Decreased (at higher dose) serum levels of the androgen precursors like androstenedione, DHEA, and DHEAS, while prostate volume and circulating levels of PSA, testosterone, free testosterone, and dihydrotestosterone were unchanged. | Kjær et al. (2015) |
| (MPX) Muscadine grape skin extract (Vitis rotundifolia) | A phase I/II Study in patients with recurrent PCa | n = 14, 500–4000 mg for 6.2–29.7 months | A higher dose of MPX is safe but serum PSA level were not reduced from baseline. | Paller et al. (2015) |
| MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin | A multicenter, placebo-controlled, two-dose, double-blinded trial in men with biochemically recurrent PCa | n = 125, 500 mg MPX (low), or 4000 mg MPX (high) daily or placebo for 12 months | No significant change in the PSA doubling time in the treated (two concentrations) versus the control group. MPX intake did not cause any adverse toxicity to the patients | Paller et al. (2018) |
| SOY ISOFLAVONES | ||||
| Genistein | A phase II placebo-controlled, randomized, double-blind clinical trial with patients before prostatectomy | n = 47, 30 mg Genistein or placebo capsules daily for 3–6 weeks. | A notable reduction in the mRNA level of androgen-related biomarker KLK4, but non-significant reduction in other PCa attributes like androgen and cell cycle. It changed the expression of several biomarkers related to PCa prediction and progression. | Lazarevic et al. (2012) |
| Soy isoflavone | A double-blinded, randomized, placebo-controlled trial | n = 86, soy isoflavone capsules (80 mg/d of total isoflavones, 51 mg/d aglucon units) for up to six weeks before scheduled prostatectomy | A short-term intervention did not change serum hormone levels, total cholesterol, or PSA but some genes related to cell cycle control and apoptosis were downregulated in the treated tumor tissue. | Hamilton-Reeves et al. (2013) |
| Isoflavone | A phase II, randomized, double-blind, placebo-controlled trial in men with rising PSA | n = 158, oral isoflavone (60 mg⁄ day) for 12 months | PSA levels did not change significantly but among all 53 patients aged ≥65 years, showed significantly less PCa incidence in the isoflavone group. | Miyanaga et al. (2012) |
| SULFORAPHANE & BROCCOLI | ||||
| Sulforaphane | A double-blinded, randomized, placebo-controlled multicenter trial in patients with increasing PSA after radical prostatectomy. | n = 78, daily oral administration of 60 mg of a stabilized free Sulforaphane for 6 months followed by 2 months without treatment (M6–M8). | Caused a significant reduction in log PSA slope and also prolonged the PSA doubling time by 86% compared to the placebo group. Sulforaphane was well-tolerated among patients. | Cipolla et al. (2015) |
| Sulforaphane-rich broccoli sprout extracts | A phase II study in patients with recurrent PCa | n = 20, 200 μmoles/day of Sulforaphane-rich extracts for a maximum period of 20 weeks | Appeared safe in the patient, prolonged on-treatment PSA doubling time but did not lead to ≥50% PSA declines in the majority of patients. | Alumkal et al. (2015) |
| Sulforaphane | A phase II single-arm study in patients with recurrent PCa | n = 20, 200 μmol of Sulforaphane extracts for up to 20 weeks per day | Lowered PSA level altogether, with an increase in PSA doubling time (6 months pre-study vs. 9.4 months on-study) and without any adverse side effects. It blocked HDAC function. | Alumkal et al. (2013) |
| Broccoli rich diet | A randomized open-label trial in patients with high-grade prostate intraepithelial neoplasia (HGPIN) | n = 22, 400 gm of broccoli/week and 400 gm peas/week for 1 year | Interacted with glutathione S-transferase mu 1 (GSTM1) and modulated signaling pathways such as TGF-β, Insulin signaling, EGF receptor associated with inflammation and carcinogenesis in the prostate. | Traka et al. (2008) |
Abbreviations: PSA, prostate-specific antigen; IGF1/3, insulin-like growth factor 1/3; EGCG, epi galloyl catechin 3 gallate; SOD, superoxide dismutase; CM-2, minichromosome maintenance protein complex; IGFBP-2/3, insulin-like growth factor binding proteins; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone-sulphate; KLK4, kallikrein 4; HDAC, histone deacetylases.