Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17[beta]-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models

• Published in: PloS one Vol. 12; no. 2; p. e0171871
• Main Authors: Kenmogne, Lucie Carolle, Roy, Jenny, Maltais, René, Rouleau, Mélanie, Neveu, Bertrand, Pouliot, Frédéric, Poirier, Donald
• Format: Journal Article
• Language: English
• Published: Public Library of Science 09-02-2017
• Subjects: Cancer cells; Care and treatment; Diagnosis; Genetic aspects; Health aspects; Investigations; Physiological aspects; Prostate cancer; Testosterone
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0171871

In the fight against androgen-sensitive prostate cancer, the enzyme 17[beta]-hydroxysteroid dehydrogenase type 3 (17[beta]-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 17[beta]-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 5[alpha]-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5[alpha]-androstane-3,17-dione and not T. Other 17[beta]-HSDs than 17[beta]-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17[beta]-HSD3 inhibitor RM-532-105 is concentrated inside tumors.