Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity.

摘要

We hypothesized that dehydroepiandrosterone metabolites or their synthetic derivatives are able to bind to the androgen receptor with low, if any, agonist activity and thus function as better antiandrogens than currently available ones. We preliminarily identified three potential dehydroepiandrosterone derivatives with marginal androgenic activity. In this project, we assessed the effects of these compounds, in comparison with classic antiandrogens clinically used, on cell proliferation/apoptosis, cell migration/invasion, and prostate-specific antigen expression in prostate cancer lines in vitro as well as on tumor growth in animal models for prostate cancer and found their inhibitory effects on androgen-mediated tumor outgrowth. We further dissected molecular mechanisms of how such compounds suppress the progression of prostate cancer and found that they could alter androgen-mediated androgen receptor functions in prostate cancer cells. Importantly, these dehydroepiandrosterone derivatives were found to possess marginal agonist effects on the activity of androgen receptor.