Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Biochem Pharmacol. 2023 Dec;218:115870. doi: 10.1016/j.bcp.2023.115870. Epub 2023 Oct 19.
Bladder cancer is one of the most common carcinomas in the human urinary system worldwide. Loperamide, known as an antidiarrheal drug, exerts anti-tumor activities against various cancers. However, the effect of loperamide on bladder cancer cells remains unclear. Our study aimed to investigate the effect of loperamide on bladder cancer and explore the underlying mechanisms. We found that loperamide suppressed the proliferation of 5637 and T24 cells in a dose-dependent manner. Loperamide treatment showed both pro-apoptotic and pro-autophagic effects on bladder cancer cells. Moreover, it was revealed that loperamide induced reactive oxygen species (ROS) accumulation, leading to the activation of c-Jun N-terminal kinase (JNK) signaling pathway. Notably, ROS scavenger N-acetyl-L-cysteine (NAC) and JNK inhibitor SP600125 effectively attenuated the induction of autophagy and apoptosis triggered by loperamide. Finally, blocking autophagy with CQ could significantly enhance the anti-cancer effect of loperamide both in vitro and in vivo. Overall, these findings demonstrated that loperamide induced autophagy and apoptosis through the ROS-mediated JNK pathway in bladder cancer cells. Our results suggest that the strategy of combining loperamide with autophagy inhibitor CQ may provide a therapeutic option for the treatment of bladder cancer.
膀胱癌是全球人类泌尿系统中最常见的癌种之一。洛哌丁胺作为一种止泻药，对多种癌症具有抗肿瘤活性。然而，洛哌丁胺对膀胱癌细胞的作用尚不清楚。我们的研究旨在探讨洛哌丁胺对膀胱癌的影响及其潜在机制。我们发现，洛哌丁胺呈剂量依赖性地抑制 5637 和 T24 细胞的增殖。洛哌丁胺处理对膀胱癌细胞表现出促凋亡和促自噬作用。此外，研究表明洛哌丁胺诱导活性氧（ROS）积累，导致 c-Jun N-末端激酶（JNK）信号通路的激活。值得注意的是，ROS 清除剂 N-乙酰-L-半胱氨酸（NAC）和 JNK 抑制剂 SP600125 可有效减弱洛哌丁胺诱导的自噬和凋亡。最后，使用 CQ 阻断自噬可以显著增强洛哌丁胺在体外和体内的抗癌作用。总的来说，这些发现表明，洛哌丁胺通过 ROS 介导的 JNK 通路诱导膀胱癌细胞发生自噬和凋亡。我们的研究结果表明，将洛哌丁胺与自噬抑制剂 CQ 联合使用的策略可能为膀胱癌的治疗提供一种新的治疗选择。
