Therapeutic Discovery A New Nonestrogenic Steroidal Inhibitor of 17b- Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen- Dependent Breast Cancer TumorGrowth Induced by Estrone
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چکیده
17b-Hydroxysteroid dehydrogenase type 1 (17b-HSD1) converts estrone (E1) into estradiol (E2) and is expressed inmany 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 16b-(m-carbamoylbenzyl)-E2 (CC-156) as a lead compound for the inhibition of 17b-HSD1, we conducted anumber of structuralmodifications to reduce its undesired residual estrogenic activity. The steroid derivative PBRM [3-(2-bromoethyl)-16b-(m-carbamoylbenzyl)-17b-hydroxy-1,3,5(10)-estratriene] emerged as a potent inhibitor of 17b-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 lineT-47Dand inmice, PBRMshowednoestrogenic 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 (AUC0–12h) 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 T47Dxenograft tumormodel in female ovariectomized athymic nudemice.After a treatmentwith 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 17b-HSD1 for the treatment of estrogen-dependent diseases such as breast cancer. Mol Cancer Ther; 11(10); 2096–104. 2012 AACR.
منابع مشابه
A new non-estrogenic steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type 1 blocks the estrogen-dependent breast cancer tumor growth induced by estrone
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A new nonestrogenic steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type I blocks the estrogen-dependent breast cancer tumor growth induced by estrone.
17β-Hydroxysteroid dehydrogenase type 1 (17β-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 basi...
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تاریخ انتشار 2012