Testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5alpha-reductase types 1 and 2. Inhibition of both 5alpha-reducatase enzymes with dutasteride was effective in reducing the incidence of prostate cancer in high risk patients. This suggests that suppression of DHT with dutasteride may have a potential therapeutic effect on prostate cancer. In this study, we examined the antitumor effects of dutasteride in vivo using a preclinical model of prostate cancer that is based on the PSA-Cre mediated inactivation of PTEN. Our findings show that monotherapy with dutasteride significantly inhibited prostate tumor growth by approximately 25%. Furthermore, the combination of dutasteride with the mTOR inhibitor, everolimus, improved tumor growth suppression compared to monotherapy with either drug. Treatment with dutasteride had a minimal effect on tumor cell proliferation; however, it significantly increased the apoptotic rate in tumors. Interestingly, treatment with dutasteride resulted in increased activation of PI3K/mTOR signaling and a reduction of STAT3 pathway activation. Moreover, increased activation of MAPK, which occurs after treatment with mTOR inhibitors, was effectively reduced with the co-administration of dutasteride. The findings from our study suggest that inhibitors of 5alpha-reductase types 1 and 2 enzymes may have a potential therapeutic value in PTEN deficient prostate cancers, in particular when co-administered with PI3K inhibitors.

Citation Format: Yurie Kura, Marco A. De Velasco, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Combining PI3K and 5alpha-reductase inhibitors improves the treatment response in a mouse model of PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 613. doi:10.1158/1538-7445.AM2014-613

©2014 American Association for Cancer Research.
2014