Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou 570228, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Molecules. 2024 Aug 7;29(16):3733. doi: 10.3390/molecules29163733.
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. It is important to discover new therapeutic regimens for treating CRC. Depression is known to be an important complication of cancer diseases. Repurposing antidepressants into anticancer drugs and exploring the combinational efficacy of antidepressants and chemotherapy are potentially good options for developing CRC treatment regimens. In this study, sertraline, an antidepressant drug, and paclitaxel, an anticancer drug, were chosen to study their antitumor effects in the treatment of colorectal cancer, alone or in combination, and to explore their underlying mechanisms. The data showed that sertraline exerted a dose-dependent cytotoxic effect on MC38 and CT26 colorectal cancer cell lines with IC values of 10.53 μM and 7.47 μM, respectively. Furthermore, sertraline synergistically sensitized chemotherapeutic agent paclitaxel efficacy in CRC cells with combination index (CI) values at various concentrations consistently lower than 1. Sertraline remarkably augmented paclitaxel-induced autophagy by increasing autophagosome formation indicated by elevated LC3-II/I ratio and promoting autophagic flux by degrading autophagy cargo receptor SQSTM1/p62, which may explain the synergistically cytotoxic effect of sertraline and paclitaxel combination therapy on CRC cells. This study provides important evidence to support repurposing sertraline as an anticancer agent and suggests a novel combinational regimen for effectively treating CRC as well as in the simultaneous treatment of CRC and depression.
结直肠癌（CRC）是全球癌症相关死亡的第二大主要原因。发现治疗 CRC 的新治疗方案非常重要。已知抑郁症是癌症疾病的重要并发症。将抗抑郁药重新用于抗癌药物，并探索抗抑郁药和化疗的联合疗效，可能是开发 CRC 治疗方案的一种很好的选择。在这项研究中，选择了抗抑郁药舍曲林和抗癌药紫杉醇，单独或联合研究它们在治疗结直肠癌中的抗肿瘤作用，并探讨其潜在的作用机制。数据显示，舍曲林对 MC38 和 CT26 结直肠癌细胞系具有剂量依赖性的细胞毒性作用，IC 值分别为 10.53 μM 和 7.47 μM。此外，舍曲林与化疗药物紫杉醇协同增敏，在各种浓度下的组合指数（CI）值均低于 1。舍曲林通过增加自噬体形成（通过升高 LC3-II/I 比值来指示）显著增强了紫杉醇诱导的自噬，并通过降解自噬货物受体 SQSTM1/p62 促进自噬流，这可能解释了舍曲林和紫杉醇联合治疗对 CRC 细胞的协同细胞毒性作用。这项研究提供了重要的证据支持将舍曲林重新用作抗癌药物，并提出了一种新的联合治疗方案，可有效治疗 CRC 以及同时治疗 CRC 和抑郁症。
