Inhibition of CYP17A1 activity by resveratrol, piceatannol and synthetic resveratrol analogues

BACKGROUND. Resveratrol (RSV) and resveratrol analogs have a potential use in prostatecancer chemoprevention due to effects on for example, cell growth, apoptosis, angiogenesis,and metastasis. However, inhibition of CYP17A1, a key enzyme in the androgen biosynthesisand a target for prostate cancer therapy, has not been explored as a possible mechanismbehind the effects on prostate cancer.METHODS. Human adrenocortical carcinoma cells, H295R, were treated with RSV, piceatannol(PIC), 3,5,40-triacetylresveratrol (RSVTA), 3,5-diacetylresveratrol (RSVDA), and 3,5,40-trimethylresveratrol (RSVTM) for 24 hr at concentrations of 1, 5, 10, 25, and 50mM. Steroidsecretion, enzyme activities, and gene expression of key steps in steroidogenesis wereinvestigated.RESULTS. Secretion of dihydroepiandrosterone (DHEA), testosterone, and cortisol weredrastically decreased by all test compounds at concentrations that did not affect cell viability.Progesterone and aldosterone secretion were increased. This steroid secretion pattern can beexplained by the demonstrated inhibition of CYP17A1 enzyme activity. The most efficientCYP17A1 inhibitors were the synthetic analogs RSVTA, RSVDA, and RSVTM. Inhibition byRSVTM was more selective on the 17,20-lyase activity than hydroxylase activity of CYP17A1.Treatment of cells with all compounds, except RSVTM, caused increased estradiol levels,which could be explained by the demonstrated inhibition of estrogen sulfate conjugation,catalyzed by SULT1E1.CONCLUSIONS. Our results on CYP17A1 inhibition of RSV and RSV analogs suggest anovel mechanism for chemoprevention of prostate cancer by resveratrol and the analogs.Especially RSVTM, which has a preferential inhibition on the 17,20-lyase activity of CYP17A1,may be a promising candidate for prostate cancer chemoprevention.