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 basis of our previous study identifying 16β-(m-carbamoylbenzyl)-E2 (CC-156) as a lead compound for the inhibition of 17β-HSD1, we conducted a number of structural modifications to reduce its undesired residual estrogenic activity. The steroid derivative PBRM [3-(2-bromoethyl)-16β-(m-carbamoylbenzyl)-17β-hydroxy-1,3,5(10)-estratriene] emerged as a potent inhibitor of 17β-HSD1 with an IC(50) 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 17β-HSD1 for the treatment of estrogen-dependent diseases such as breast cancer.
Laboratory of Medicinal Chemistry, CHUQ (CHUL)-Research Center, 2705 Laurier Boulevard, Quebec G1V 4G2, Canada.
Diana
D
Ayan
René
R
Maltais
Jenny
J
Roy
Donald
D
Poirier
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000097:blood / Q000494:pharmacology*; D004970:Estrone / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
C506487:ESR1 protein, human; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases