A New Nonestrogenic Steroidal Inhibitor of 17 beta-Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen-Dependent Breast Cancer Tumor Growth Induced by Estrone

作者：Ayan Diana; Maltais Rene; Roy Jenny; Poirier Donald^*

来源：Molecular Cancer Therapeutics, 2012, 11(10): 2096-2104.

DOI：10.1158/1535-7163.MCT-12-0299

17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) converts estrone (E1) into estradiol (E2) and is expressed in many steroidogenic tissues and breast cancer cell lines. Because the potent estrogen E2 stimulates the growth and development of hormone-dependent diseases, inhibition of the final step of E2 synthesis is considered a promising strategy for the treatment of breast cancer. On the basis of our previous study identifying 16 beta-(m-carbamoylbenzyl)-E2 (CC-156) as a lead compound for the inhibition of 17 beta-HSD1, we conducted a number of structural modifications to reduce its undesired residual estrogenic activity. The steroid derivative PBRM [3-(2-bromoethyl)-16 beta-(m-carbamoylbenzyl)-17 beta-hydroxy-1,3,5(10)-estratriene] emerged as a potent inhibitor of 17 beta-HSD1 with an IC50 value of 68 nmol/L for the transformation of E1 into E2. When tested in the estrogen-sensitive breast cancer cell line T-47D and in mice, PBRM showed no estrogenic activity in the range of concentrations tested. Furthermore, with the purpose of evaluating the bioavailability of PBRM and CC-156 injected subcutaneously (2.3 mg/kg), we measured their plasmatic concentrations as a function of time, calculated the area under the curve (AUC(0-12h)) and showed a significant improvement for PBRM (772 ng*h/mL) compared with CC-156 (445 ng*h/mL). We next tested the in vivo efficiency of PBRM on the T-47D xenograft tumor model in female ovariectomized athymic nude mice. After a treatment with PBRM, tumor sizes in mice stimulated with exogenous E1 were completely reduced at the control group level (without E1 treatment). As a conclusion, PBRM is a promising nonestrogenic inhibitor of 17 beta-HSD1 for the treatment of estrogen-dependent diseases such as breast cancer. Mol Cancer Ther; 11(10); 2096-104.

• 出版日期2012-10