Blum Ciara B, Dohrmann McCarlie-Jayne, McCarthy Lucia, McMenamin Milli, O'Callaghan Liam A
School of Medicine and Dentistry, Griffith University, Southport, Queensland, Australia.
Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia.
Pharmacol Res Perspect. 2025 Oct;13(5):e70168. doi: 10.1002/prp2.70168.
Drug repurposing offers a cost-effective and time-efficient strategy for identifying new cancer therapies. Sertraline, a widely prescribed selective serotonin reuptake inhibitor (SSRI), has shown promising anticancer properties through modulation of key pathways involved in tumor survival, stress adaptation, and therapeutic resistance. This scoping review systematically evaluates the current evidence on sertraline's anticancer mechanisms, efficacy, and translational potential. A systematic search of PubMed, EMBASE, Scopus, and Web of Science was conducted in accordance with PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, mechanisms, assays, and outcomes were extracted and synthesized. Of 97 screened articles, 67 met inclusion criteria, comprising 56 preclinical studies, nine population-based studies, and two mixed-methods reports. Sertraline induces apoptosis via mitochondrial dysfunction, caspase activation, and Bcl-2 downregulation, disrupts autophagy and the unfolded protein response, and impairs serine/glycine metabolism through SHMT inhibition. It also suppresses oncogenic signaling via mTOR and TCTP modulation. In vivo studies confirmed tumor growth inhibition in various cancer models, including breast, lung, glioblastoma, and liver. Sertraline enhances the efficacy of chemotherapy, radiotherapy, and targeted therapies by sensitizing resistant cells, modulating immune responses, and impairing metabolic recovery. Retrospective studies suggest no increased cancer risk with SSRI use and hint at protective associations in select malignancies. While current evidence is predominantly preclinical, sertraline's multi-targeted action and established safety profile support its candidacy for repurposing. Further translational research and biomarker-driven clinical trials are warranted to validate its therapeutic niche and optimize its integration into oncology.
药物重新利用为确定新的癌症治疗方法提供了一种具有成本效益且节省时间的策略。舍曲林是一种广泛使用的选择性5-羟色胺再摄取抑制剂（SSRI），通过调节参与肿瘤存活、应激适应和治疗抗性的关键途径，已显示出有前景的抗癌特性。本综述系统地评估了关于舍曲林抗癌机制、疗效和转化潜力的现有证据。根据PRISMA-ScR指南，对PubMed、EMBASE、Scopus和科学网进行了系统检索。符合条件的研究包括体外、体内和临床研究。提取并综合了关于癌症类型、机制、检测方法和结果的数据。在筛选的97篇文章中，67篇符合纳入标准，包括56项临床前研究、9项基于人群的研究和2篇混合方法报告。舍曲林通过线粒体功能障碍、半胱天冬酶激活和Bcl-2下调诱导细胞凋亡，破坏自噬和未折叠蛋白反应，并通过抑制丝氨酸羟甲基转移酶损害丝氨酸/甘氨酸代谢。它还通过调节mTOR和TCTP抑制致癌信号传导。体内研究证实了在各种癌症模型中，包括乳腺癌、肺癌、胶质母细胞瘤和肝癌中，舍曲林对肿瘤生长的抑制作用。舍曲林通过使耐药细胞敏感、调节免疫反应和损害代谢恢复，增强了化疗、放疗和靶向治疗的疗效。回顾性研究表明，使用SSRI不会增加癌症风险，并且在某些恶性肿瘤中提示有保护关联。虽然目前的证据主要是临床前的，但舍曲林的多靶点作用和已确立的安全性概况支持其重新利用的候选资格。有必要进行进一步的转化研究和生物标志物驱动的临床试验，以验证其治疗优势，并优化其在肿瘤学中的应用。
