Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity
Annual summary rept. 1 Jul 2013-30 Jun 2014
JOHNS HOPKINS UNIV BALTIMORE MD
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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 previously identified three potential compounds with marginal androgenic activity. We also demonstrated that, using multiple prostate cancer lines, these compounds could inhibit androgen-induced growth of androgen receptor-positive cells in vitro but that treatment with each compound resulted in modest decreases in tumor growth in mouse models for prostate cancer. We here assessed whether the dehydroepiandrosterone derivatives altered androgen-mediated androgen receptor functions, including androgen receptor mRNAprotein stability, androgen receptor NC-terminal interaction, androgen receptorandrogen receptor coregulator interactions, and androgen receptor nuclear translocation, in prostate cancer cells. All three compounds were found to interrupt interactions between N-terminus and C-terminus of androgen receptor as well as androgen receptor and several androgen receptor coregulators but failed to affect the stability and nuclear translocation of androgen receptor.
- Medicine and Medical Research