Table 1.

Selected published human clinical trials using natural chemopreventive agents against PCa.

Chemopreventive Agent	Study design		Study Outcome	Ref
	Dose and Duration	Subjects/Sample size/Phase
Tea polyphenols
Green tea, black tea or water	6 cups/day for 3 to 8 weeks	PCa intervention, N=113; Phase II	NF-κB staining in radical prostatectomy tissue, urinary 8-OHdG and serum PSA levels were significantly decreased in green tea, but not in black tea group.	[18]
Green tea or water	6 cups/day for 3 to 8 weeks	Clinically localized PCa, N=17	Methylated and nonmethylated forms of EGCG were detectable in prostatectomy tissue.	[19]
Green tea, black tea or a caffeine-matched soda control	1.42 L daily for 5 day	Prostatectomy scheduled Patients, N=20	Tea polyphenols and theaflavins were found bioavailable in the prostate, and therefore may be effective in the management of PCa.	[17]
Green tea catechins (GTC)	3 × 200 mg capsules; total 600 mg) or placebo control daily for 1 year	HGPIN volunteers, N=60	Decrease in the tumor incidence and PSA level, improved quality of life, and reduced lower urinary tract symptoms in GTC-supplemented men. In a follow-up study, further reduction in PCa were noticed suggesting long-lasting effect of GTC.	[20, 21]
Polyphenon E	400 mg EGCG/day or placebo for 1 year	HGPIN and/or ASAP N=97	No significant difference in the number of PCa cases, however, a decrease in PSA was reported in EGCG group.	[22]
Polyphenon E	1.3 g of tea polyphenols including 800 mg EGCG or placebo daily for around 6 weeks	Prostatectomy scheduled Patients, N=26; Phase II	Significant decrease in serum levels of PSA, HGF, IGF-I, IGFBP-3, and VEGF in men with PCa.	[23]
Polyphenon E	800 mg EGCG or placebo daily for 3–6 weeks	Prostatectomy scheduled Patients, N=50; Phase II	Favorable but statistically insignificant changes in systemic and tissue biomarkers including PSA.	[24]
Vitamins and Minerals
Vitamin D	Calcitriol 0.5 μg/kg) or placebo weekly for 4 weeks	Histologically confirmed PCa, N=39	Calcitriol was found to downregulate vitamin D receptor expression in human PCa.	[82]
Vitamin D analog	1α-hydroxyvitamin D2; 10 μg orally or placebo daily for 28 days	Clinically localized PCa and HGPIN, N=60, Phase II	Biologic activity of 1α-hydroxyvitamin D2 was minimal in both serum and tissue, and TGF-ß2 was the only biomarker found significantly reduced.	[28]
Vitamin E	400 IU/day of all rac-α-tocopheryl acetate or placebo over 5 years (planned for 7–12 years).	Healthy with negative digital rectal exam, N=35,533, Phase III	There were non-significant increased risks of PCa in the vitamin E group. In subsequent follow-up study, vitamin E supplementation was found to be associated with significant increase in the risk of PCa.	[35, 36]
Vitamin E 2,2,5,7,8-pentamethyl-6-chromanol	APC-100, 900–2400 mg orally daily for 28 days	Castrate-resistant PCa (CRPC), N=20, Phase I/IIa	APC-100, which act as both antioxidant as well as antiandrogen, was found to have a slightly better response, as 5 out of 20 patients had stable disease. However, APC-100 was not detectable in plasma.	[39]
Calcium carbonate	3 g; 1,200 mg of calcium or placebo, daily for 4 years	Colorectal adenoma chemoprevention trial, N=673	There were 33 PCa cases in the calcium-treated group vs 37 in the placebo group after a mean follow-up of 10.3 years, suggesting protective effects of calcium.	[83]
Selenium
Selenium	As selenized yeast; 200 μg/day) or placebo for a mean of 4.5 years	Men with history of non-melanoma skin cancer, N=974	Selenium was found to be associated with a significant reduction in the PCa incidence (secondary endpoint), in patients with lower baseline PSA and plasma selenium levels.	[52, 84–86]
Selenium	As L-selenomethionin e; 200 μg/day) over 5 years (planned for 7-years) 12	Healthy men with negative digital rectal exam, N=35,533, Phase III	No preventive effects against PCa were found. However, supplementation in men with high Se status increased the risk of high-grade PCa.	[35, 87]
Selenium	As selenized yeast; years 200 or 400 μg/day up to 5	Men with ≥1 negative sextant prostate biopsy, N=699, Phase III	No effect on incidence of PCa or PSA velocity in men at high risk was found.	[55, 88]
Selenium	As selenized yeast; years 200 or 800 μg/day up to 5	Localized nonmetastatic PCa patients, N=140, Phase II	No significant effect of selenium on PSA velocity was seen. Men in the highest quartile supplemented with the highest dose showed an increase in PSA velocity.	[57, 89]
Selenium	As selenomethionin e; 200 μg/day) over a 3-year period.	Men diagnosed with HGPIN, N=423, Phase III	Selenium had no effect on PCa risk, although a subset analysis found a trend of reduced PCa in Se vs placebo patients in the lowest quartile of baseline plasma Se levels.	[56, 90]
Soy and isoflavones
Dietary soy	High (2 servings of soy foods/day) and low (no added soy) via diet for 3 months	Healthy men aged 58.7+/−7.2 years, N=24	The study found 14% decline in serum PSA levels, though statistically not significant, in the high soy diet in contrast to the low soy diet.	[63]
Soy beverage	500 mL daily for 6 month	Men with rising PSA after radical radiation, N=29	A declining trend in PSA levels and a trend towards >2 times prolongation of PSA doubling time in 41% of subjects.	[64]
Isoflavone+	As soy protein drink; 83 mg/day, or isoflavone drink for 12 months	Healthy men aged 50–80 years, N=112	No significant change in serum PSA level, velocity, or PCa incidence in isoflavone treatment group, or in other prostate conditions that affect serum PSA levels.	[65]
Isoflavone	60 mg/day or placebo for 12 months	Men with rising PSA, N= 158, Phase II	No significant change in PSA levels after isoflavone treatment. However, 53 patients aged ≥65 years, showed significantly lower PCa incidence in the isoflavone group.	[67]
Soy protein isolate	107 or <6 or 0 mg/day isoflavones for 6 months.	High risk PCa patients, N=58	Isoflavone-rich soy protein significantly reduced AR expression, but no change in estrogen receptor-β or circulating hormones in men at high risk of PCa.	[68]
Isoflavones	5g/day including 450 mg genistein, 300 mg daidzein, or placebo for 6 months	Low-volume PCa patients, N=53	No significant reduction in PSA levels were found in men with low-volume PCa.	[69]
Isoflavones	80 mg/day for up to 6 week	Patients with localized PCa, N=86, Phase II	No significant change in serum hormone levels, total cholesterol, or PSA after short-term intake of soy isoflavones.	[66]
Genistein	30 mg/day or placebo for 3–6 weeks	Patients with localized PCa, N=47, Phase II	Significant reduction in the androgen-related biomarker KLK4, but no significant changes in proliferation-, cell cycle-, apoptosis-related biomarkers.	[70]
Resveratrol and Grapes
Resveratrol	150 or 1,000 mg or placebo daily for 4 months	Men suffering from the metabolic syndrome, N=66	High dose of resveratrol was associated with lower serum levels of androstenedione, dehydroepiandrosterone-sulphate, and dehydroepiandrosterone. However, there was no effect on prostate volume.	[72]
Muscadine grape skin extract	(500–4,000 mg) for 28 days	Recurrent PCa N=14; phase I/II	No patients exhibited a maintained fall in serum PSA from baseline.	[75]