Question: CYP17 inhibitors have been used as androgen-depleting drugs for androgen-dependent diseases such as advanced prostate cancer. However, inhibition of the 17α-hydroxylase and 17,20-lyase activities of CYP17 by current inhibitors leads to elevation of corticosteroid production, which increases risk of cardiovascular diseases. There is a need to develop a new CYP17 inhibitor without cardiovascular side effects. Methods: Polyphenols resemble to steroids in structure. In this study, we explore the possible application of natural and synthetic polyphenols in CYP17 blockage using human adrenocortical H295R cells as a model. Results: Resveratrol is the most potent CYP17 inhibitor among the examined polyphenols. The value of IC50 is approximately 4 μM. Resveratrol also inhibits CYP21 but to a lesser extent as compared with CYP17. Because the 21α-hydroxylase activity of CYP21 is indispensable for corticosteroid biosynthesis, the dual inhibition of CYP17 and CYP21 by resveratrol prevents corticosteroid elevation following CYP17 blockage. Resveratrol inhibits CYP17 and CYP21 mainly at the level of enzyme activity rather than enzyme abundance and cytochrome P450 electron transfer. Daidzein inhibits 3βHSD2 (3β-hydroxysteroid dehydrogenase type II) in addition to CYP17 and CYP21. Therefore, dehydroepiandrosterone accumulation is accompanied with androgen biosynthetic impairment under daidzein treatment. On the other hand, androgen and cortisol secretion is increased or remains normal under α-naphthoflavone and β-naphthoflavone treatments. Conclusion: Our findings suggest a potential application of resveratrol in androgen deprivation therapy.
