Poirier Donald, Roy Jenny, Maltais René, Weidmann Cindy, Audet-Walsh Étienne
Endocrinology and Nephrology Unit, CHU de Québec Research Center-Université Laval, Pavillon CHUL, Québec, QC G1V 4G2, Canada.
Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada.
Cancers (Basel). 2023 Jun 2;15(11):3033. doi: 10.3390/cancers15113033.
The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect in combination with RM-581. These findings suggest that RM-581 may have an action that is not directly associated with the hormonal pathway of androgens. Furthermore, RM-581 completely blocks tumor growth in LAPC-4 xenografts when given orally at 3, 10, and 30 mg/kg in non-castrated (intact) nude mice. During this study, an accumulation of RM-581 was observed in tumors compared to plasma (3.3-10 folds). Additionally, the level of fatty acids (FA) increased in the tumors and livers of mice treated with RM-581 but not in plasma. The increase was greater in unsaturated FA (21-28%) than in saturated FA (7-11%). The most affected FA were saturated palmitic acid (+16%), monounsaturated oleic acid (+34%), and di-unsaturated linoleic acid (+56%), i.e., the 3 most abundant FA, with a total of 55% of the 56 FA measured. For cholesterol levels, there was no significant difference in the tumor, liver, or plasma of mice treated or not with RM-581. Another important result was the innocuity of RM-581 in mice during a 28-day xenograft experiment and a 7-week dose-escalation study, suggesting a favorable safety window for this new promising drug candidate when given orally.
氨基甾体衍生物RM-581高效阻断雄激素依赖性（AR）前列腺癌VCaP、22Rv1和LAPC-4细胞的生长。值得注意的是，与恩杂鲁胺和阿比特龙相比，RM-581在LAPC-4细胞中表现出更强的抗增殖活性，这两种药物与RM-581联合使用时具有协同效应。这些发现表明，RM-581可能具有一种与雄激素激素途径不直接相关的作用。此外，在未去势（完整）裸鼠中，当以3、10和30mg/kg的剂量口服给药时，RM-581可完全阻断LAPC-4异种移植瘤的生长。在这项研究中，与血浆相比，在肿瘤中观察到RM-581有蓄积（3.3至10倍）。此外，用RM-581治疗的小鼠的肿瘤和肝脏中脂肪酸（FA）水平升高，但血浆中未升高。不饱和脂肪酸（21-28%）的增加幅度大于饱和脂肪酸（7-11%）。受影响最大的脂肪酸是饱和棕榈酸（+16%）、单不饱和油酸（+34%）和双不饱和亚油酸（+56%），即3种最丰富的脂肪酸，在所测量的56种脂肪酸中占总数的55%。对于胆固醇水平，用RM-581治疗或未治疗的小鼠的肿瘤、肝脏或血浆中均无显著差异。另一个重要结果是，在为期28天的异种移植实验和为期7周的剂量递增研究中，RM-581对小鼠无害，这表明口服这种新的有前景的候选药物时具有良好的安全范围。
