The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use.
药物重定位策略作为一种发现已上市药物新治疗用途的手段，在癌症治疗领域日益受到关注。帕罗西汀作为一种常用于治疗抑郁症的选择性5-羟色胺再摄取抑制剂，已显示出抗癌潜力。然而，其在三阴性乳腺癌中的具体作用机制尚不明确。本研究旨在探讨帕罗西汀在体外对三阴性乳腺癌细胞的单独及联合用药效果。通过MTT法检测细胞活力，流式细胞术分析细胞凋亡，并采用RNA测序与Western blot技术探究其对信号通路的影响。此外，通过皮下移植瘤模型评估联合用药对肿瘤生长的体内抑制作用。研究结果表明，帕罗西汀可能通过影响PI3K/AKT/mTOR通路及诱导细胞保护性自噬，激活Ca2+依赖性线粒体介导的内源性凋亡途径。在体内实验中，帕罗西汀与化疗药物联用对4T1肿瘤生长显示出中等程度的抑制作用。这些发现提示帕罗西汀可能通过调控关键分子通路影响三阴性乳腺癌进程，为增强化疗敏感性及开发临床联合治疗方案提供了重要参考。
Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux
肿瘤(癌症)患者之家