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

Abstract

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.

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3

“…The 17b-HSD3 enzyme catalyzes the biosynthesis of approximately 50% of the total amount of androgen in men (Mendonca et al, 2017). Therefore, 17b-HSD3 has been recognized as a promising therapeutic target for reducing the levels of the circulating androgens and suppressing the proliferation of androgen-sensitive tumors (Kenmogne et al, 2017). The inhibition of 17b-HSD3 might provide an effective treatment strategy for hormone-dependent prostate cancer.…”

A- and D-Ring Structural Modifications of an Androsterone Derivative Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3: Chemical Synthesis and Structure–Activity Relationships

“…Thus, the lack of androgenic effect should be addressed using other methods such as yeast-based reporter gene assay, 44 or AR transcriptional amplification system. 26 Using this latter transcriptional activity assay, we thus previously observed no androgenic activity for the lead compound 1, but a cytotoxic activity was observed at the higher concentration tested of 2 μM. 26 However, a compound that can reduce the proliferation of cancer cells is, however, interesting in itself and, for this reason, we considered the proliferation of cancer cells as an assay providing interesting information.…”

“…26 Using this latter transcriptional activity assay, we thus previously observed no androgenic activity for the lead compound 1, but a cytotoxic activity was observed at the higher concentration tested of 2 μM. 26 However, a compound that can reduce the proliferation of cancer cells is, however, interesting in itself and, for this reason, we considered the proliferation of cancer cells as an assay providing interesting information. Furthermore, since some of the new inhibitors are based on an estrane backbone, instead of the androstane backbone of 1, we also addressed their potential estrogenic activity.…”

“…25 Although RM-532-105 significantly accumulated inside the tumor of LAPC-4 xenografts, it was not able to reduce the growth of tumor. 26 Recently, we have reported the synthesis and biological activity of two RM-532-105 stereoisomers, 27 the first one possessing an inversed hydrogen on carbon 5 (5β-H instead of 5α-H) while the second one bears an inversed methyl carbon attached to C13 (13α-CH 3 instead of 13β-CH 3 ). Both modifications were carried out to explore the impact on 17β-HSD3 inhibitory activity, androgenic profile, and metabolic stability by structural modifications on the A-and D-ring shapes, respectively.…”

“…Moreover, this lead compound significantly decreased T and DHT levels when administered subcutaneously in rats . Although RM-532-105 significantly accumulated inside the tumor of LAPC-4 xenografts, it was not able to reduce the growth of tumor …”