Breast cancer is one the most aggressive cancer worldwide, especially Pakistan due to limited therapeutic options. This study was conducted to repurpose the use of selective serotonin reuptake inhibitors (SSRIs), in the treatment of breast cancers, and merit to pursue drug re-positioning in oncology. Anti-proliferative activity of SSRIs, such as fluoxetine, paroxetine, and sertraline hydrochloride on the growth of AU-565, MCF-7, MDA-MB-231, and BT-474 breast cancer cell lines, along with human fibroblast BJ cells was determined in vitro. Changes in nuclear morphology (DAPI staining), and induction of apoptosis (flow cytometry, and caspase-3 activation) were also studied. Sertraline hydrochloride most effectively inhibited the growth of breast cancer cells in vitro. Therefore, pharmacological mechanism involved in sertraline mediated cell death was investigated in HER2+ AU565 cell line. Enhanced nuclear fragmentation, increased Annexin (+) cells, and caspase-3/7 activation indicated that sertraline-mediated cell death could be a result of BCl2-independent apoptosis as evidenced by expression of Bax, and BCl2 genes. Taken together, our results identified sertraline hydrochloride, as a potential candidate for the treatment of HER2-positive breast cancer. Even though these are in vitro results, this study opens great opportunity in the field of drug repurposing for the development of chemotherapeutic agents.

中文翻译：

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抗抑郁药盐酸舍曲林通过诱导细胞凋亡和细胞周期阻滞抑制 HER2+ AU565 乳腺癌细胞系的生长

乳腺癌是全球最具侵袭性的癌症之一，尤其是巴基斯坦，因为治疗选择有限。本研究旨在重新利用选择性 5-羟色胺再摄取抑制剂 (SSRIs) 在乳腺癌治疗中的用途，以及在肿瘤学中进行药物重新定位的价值。SSRIs，如氟西汀、帕罗西汀和盐酸舍曲林对 AU-565、MCF-7、MDA-MB-231 和 BT-474 乳腺癌细胞系以及人成纤维细胞 BJ 细胞的生长具有抗增殖活性体外测定。还研究了细胞核形态（DAPI 染色）和凋亡诱导（流式细胞术和 caspase-3 激活）的变化。盐酸舍曲林在体外最有效地抑制乳腺癌细胞的生长。因此，在 HER2+ AU565 细胞系中研究了涉及舍曲林介导的细胞死亡的药理机制。核分裂增强、膜联蛋白 (+) 细胞增加和 caspase-3/7 活化表明舍曲林介导的细胞死亡可能是 BCl2 非依赖性细胞凋亡的结果，如 Bax 和 BCl2 基因的表达所证明。总之，我们的结果确定盐酸舍曲林是治疗 HER2 阳性乳腺癌的潜在候选药物。尽管这些是体外结果，但这项研究在药物再利用领域为开发化疗药物开辟了巨大的机遇。