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.
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.
复制标题
DOI：
10.1371/journal.pone.0171871
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Poirier D
中科院分区：
文献类型：
--
作者：
Kenmogne LC;Roy J;Maltais R;Rouleau M;Neveu B;Pouliot F;Poirier D
在对抗雄激素敏感的前列腺癌中，考虑到 17β-羟基类固醇脱氢酶 3 型 (17β-HSD3) 在雄激素类固醇形成中的关键作用，它是一个有吸引力的治疗靶点。在本研究中，我们试图评估化合物 RM-532-105（一种作为 17β-HSD3 抑制剂开发的雄酮衍生物）在雄激素敏感 LAPC-4 细胞异种移植到裸鼠的前列腺癌模型中的体内功效。 RM-532-105不抑制4-雄烯-3,17-二酮（4-dione）诱导的肿瘤生长；相反，肿瘤内雄激素睾酮（T）和二氢睾酮（DHT）的水平增加。然而，在血浆中，DHT 水平增加，但 T 水平却没有增加。在故障排除实验中，RM-532-105 的非雄激素潜力通过两种不同的测定（LAPC-4 增殖和雄激素受体转录活性测定）得到证实。 5α-还原酶也被发现是 LAPC-4 细胞中代谢 4-二酮的主要酶，产生 5α-雄甾烷-3,17-二酮而不是 T。除 17β-HSD3 之外的其他 17β-HSD 似乎负责雄激素合成。通过 LAPC-4 细胞的实验，我们偶然发现了一个有趣的发现，即 17β-HSD3 抑制剂 RM-532-105 集中在肿瘤内部。
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.