前列腺癌（PCa）是男性中最常见的癌症，也是西方国家第二大死因。在临床上，筛选药物并开发新的治疗方法来治疗前列腺癌具有重要意义。本研究证明，BML-275通过拮抗mTOR活性在前列腺癌中展现出强效的抗肿瘤效果。在培养的前列腺癌细胞中，BML-275处理降低了c-Myc和survivin的表达水平，促进了p53的激活，从而诱导了p21/cyclin D1/CDK4/6依赖的细胞周期G1/S停滞。因此，BML-275抑制了细胞增殖，并诱导了线粒体介导的细胞凋亡。此外，BML-275处理触发了自噬。有趣的是，自噬的EACC介导抑制并不影响BML-275诱导的增殖和凋亡。裸鼠致瘤实验证实了BML-275抑制前列腺癌生长，并诱导前列腺癌细胞凋亡和自噬的效果。机械上，BML-275处理在体外和体内下调了PI3K/AKT和AMPK途径的活性。重要的是，PI3K/AKT和AMPK信号的共同下游负调控蛋白mTOR被激活为不活化状态，这可能与凋亡和自噬的诱导有关。通过MHY1485的药理激活，mTOR的诱导由BML-275引起的凋亡和自噬被废除。分子对接结果表明，BML-275能够结合到mTOR蛋白上FKRP12-rapamycin结合位点，从而可能像拉帕霉素一样对mTOR具有相同的抑制活性。因此，这些发现表明，BML-275通过靶向mTOR抑制诱导前列腺癌中的线粒体介导的凋亡和自噬。BML-275可能是前列腺癌治疗的潜在候选药物。版权所有 © 2023. Elsevier B.V.出版。

Prostate cancer (PCa) is the most frequently diagnosed cancer among men and the second leading cause of death in Western countries. Clinically, screening drugs and develop developing new therapeutics to treat PCa is of great significance. In this study, BML-275 was demonstrated to exert potent antitumor effects in PCa by antagonizing mTOR activity. In cultured PCa cells, BML-275 treatment reduced the expression levels of c-Myc and survivin, promoted the activation of p53, and thereby induced p21/cyclin D1/CDK4/6-dependent cell cycle G1/S arrest. As a result, BML-275 inhibited cellular proliferation and induced mitochondrial-mediated apoptosis. In addition, BML-275 treatment triggered autophagy. Interestingly, EACC-mediated suppression of autophagy did not affect BML-275-induced proliferation and apoptosis. Nude mouse tumorigenic experiments also confirmed that BML-275 inhibited PCa growth, induced PCa cell apoptosis and autophagy. Mechanistically, the activities of PI3K/AKT and AMPK pathways were downregulated by BML-275 treatment in vitro and in vivo. Importantly, mTOR, a common downstream negative protein of PI3K/AKT and AMPK signaling, was induced to inactivate, which may be associated with the induction of apoptosis and autophagy. The pharmacological activation of mTOR by MHY1485 abolished the induction of apoptosis and autophagy of BML-275. Molecular docking results showed that BML-275 can bind to the FKRP12-rapamycin binding site on mTOR protein, and thereby may have the same inhibitory activity on mTOR as rapamycin. Thus, these findings indicated that BML-275 induces mitochondrial-mediated apoptosis and autophagy in PCa by targeting mTOR inhibition. BML-275 may be a potential candidate for the treatment of PCa.Copyright © 2023. Published by Elsevier B.V.