3β-Acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity

Abstract

The majority of available antiandrogens have been reported to possess agonist activity to induce prostate-specific antigen, which might result in antiandrogen withdrawal syndrome. Here we report the identification of 3β-acetoxyandrost-1,5-diene-17-ethylene ketal (ADEK) from dehydroepiandrosterone metabolites and derivatives as a potent antiandrogen. We found ADEK could interrupt androgen binding to the androgen receptor (AR) and suppress androgen-induced transactivations of WT AR and a mutant AR in prostate cancer cells. ADEK inhibited prostate-specific antigen expression as well as growth in LNCaP prostate cancer cells stimulated by androgen. Importantly, ADEK had only marginal agonist effects, as compared with commonly used antiandrogens such as hydroxyflutamide and bicalutamide, leading to a lower possibility of inducing withdrawal response. Moreover, ADEK could block an adrenal androgen androstenediol-induced AR transactivation that hydroxyflutamide and bicalutamide failed to block. These unique antiandrogenic activities make ADEK a potential therapeutic compound that might be able to inhibit AR-mediated prostate cancer progression. Further in vivo studies might facilitate the development of a better antiandrogen for the treatment of prostate cancer.

Identification of steroid derivatives that function as potent antiandrogens

“…We showed that many DHEA metabolites, including ADEK, possess some estrogen activity, 15,16 suggesting that ADEK might cause not only castration effect but also some side effects, such as cardiovascular toxicity in vivo. Because of these unfavorable side effects, estrogens (e.g., DES) are rarely used as first-line hormonal treatment in spite of the evidence suggesting an additional benefit, a direct cytotoxic effect of estrogens through both estrogen receptor (ER)-dependent and ER-independent pathways in prostate cancer cells.…”

“…6,9,11,16,17 PSA-Luc containing a natural 6.0 kb promoter and a synthetic (ARE)4-Luc containing 4 copies of androgen response element (ARE) were kindly provided by Dr. A. Mizokami (Kanazawa University, Kanazawa, Japan) and Dr. M.L. Lu (Harvard Medical School, Boston, MA), respectively.…”

“…9 We then found that ADEK has anti-Adiol effect on AR transcription in prostate cancer cells. 16 In our study, we also measured MMTV-Luc activity to determine whether HAD and OAK inhibit Adiol-induced AR transcription. Adiol at 2.5 nM increases AR transcriptional activity in PC-3 (Fig.…”

“…The affinity of ligands for the AR was assessed by incubating whole cell extracts of LNCaP or COS-1 with transfected WT AR with 1 nM [ 3 H]-R1881 in the presence of various concentrations (1-10,000 nM) of unlabeled DHT, HF, HAD, OAK or ADEK. As described previously, 16 …”

“…We have synthesized a number of steroids and tested their antiandrogenic activity vs. Adiol and DHT. 15,16 The most effective was 3b-acetoxyandrosta-1,5-diene-17-one ethylene ketal (ADEK), which inhibits both DHT-and Adiol-induced AR transcription, PSA expression and growth in prostate cancer cells. Significantly, ADEK has marginal androgenic activity and a strong AR coactivator, ARA70, which has been shown to enhance agonist activity of clinically used antiandrogens, 17,18 fails to induce it.…”