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

Abstract

Resveratrol (RSV) and resveratrol analogs have a potential use in prostate cancer chemoprevention due to effects on for example, cell growth, apoptosis, angiogenesis, and metastasis. However, inhibition of CYP17A1, a key enzyme in the androgen biosynthesis and a target for prostate cancer therapy, has not been explored as a possible mechanism behind the effects on prostate cancer. Human adrenocortical carcinoma cells, H295R, were treated with RSV, piceatannol (PIC), 3,5,4'-triacetylresveratrol (RSVTA), 3,5-diacetylresveratrol (RSVDA), and 3,5,4'-trimethylresveratrol (RSVTM) for 24 hr at concentrations of 1, 5, 10, 25, and 50 µM. Steroid secretion, enzyme activities, and gene expression of key steps in steroidogenesis were investigated. Secretion of dihydroepiandrosterone (DHEA), testosterone, and cortisol were drastically decreased by all test compounds at concentrations that did not affect cell viability. Progesterone and aldosterone secretion were increased. This steroid secretion pattern can be explained by the demonstrated inhibition of CYP17A1 enzyme activity. The most efficient CYP17A1 inhibitors were the synthetic analogs RSVTA, RSVDA, and RSVTM. Inhibition by RSVTM 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. Our results on CYP17A1 inhibition of RSV and RSV analogs suggest a novel 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.