Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models.
In the fight against androgen-sensitive prostate cancer, the enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17β-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione); rather, the levels of the androgens testosterone (T) and dihydrotestosterone (DHT) increased within the tumors. In plasma, however, DHT levels increased but T levels did not. In troubleshooting experiments, the non-androgenic potential of RM-532-105 was confirmed by two different assays (LAPC-4 proliferation and androgen receptor transcriptional activity assays). The enzyme 5α-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5α-androstane-3,17-dione and not T. Other 17β-HSDs than 17β-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17β-HSD3 inhibitor RM-532-105 is concentrated inside tumors.
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), Québec, Québec, Canada.
Lucie Carolle
LC
Kenmogne
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), Québec, Québec, Canada.
Jenny
J
Roy
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), Québec, Québec, Canada.
René
R
Maltais
CHU de Québec - Research Center, Axe Cancer, Québec, Québec, Canada.
Mélanie
M
Rouleau
CHU de Québec - Research Center, Axe Cancer, Québec, Québec, Canada.
Bertrand
B
Neveu
CHU de Québec - Research Center, Axe Cancer, Québec, Québec, Canada.|Department of Surgery, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
Frédéric
F
Pouliot
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), Québec, Québec, Canada.|Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
Donald
D
Poirier
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000731:Androstanes / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D000731:Androstanes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000588579:RM-532-105; D013449:Sulfonamides; D013196:Dihydrotestosterone; D015067:17-Hydroxysteroid Dehydrogenases