Wang Jiahui, Yue Zhouli, Bu Jingjing, Quan Siqi, Guo Roujia, Wang Menglin, Shen Jiduo, Li Min, Li Yucheng
Collaborative Innovation Center of Research and Development on the Whole Industry Chain for Yu-Yao in Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
Med Oncol. 2025 Jul 22;42(8):364. doi: 10.1007/s12032-025-02919-7.
Depressive symptoms are recognized contributors to breast cancer progression; while previous studies have investigated the role of antidepressants in breast cancer, their therapeutic potential remains insufficiently and systematically explored. This study systematically evaluated the anti-tumor efficacy of six clinically used antidepressants (escitalopram, amitriptyline, fluoxetine, paroxetine, desvenlafaxine, and duloxetine) in 4T1 (murine triple negative) and MCF-7 (human ER/HER2) breast cancer cells. The results indicated that duloxetine exhibited the most potent cytotoxicity, with IC values of 6.94 μM in 4T1 and 16.16 μM in MCF-7 cells. Although less potent than docetaxel, duloxetine still exhibited significant anti-proliferative, anti-migratory, and pro-apoptotic effects. In vivo, duloxetine (10-30 mg/kg) significantly suppressed tumor growth in 4T1-bearing mice, accompanied by decreased Ki-67 expression and increased E-cadherin. Moreover, duloxetine significantly inhibited the phosphorylation of AKT and mTOR, thereby promoting autophagy activation, as evidenced by increased LC3 expression and decreased P62 levels. Additionally, duloxetine promotes apoptosis by upregulating Bax and downregulating Bcl-2 expression both in vitro and in vivo. These findings reveal that duloxetine exerts anti-breast cancer effects through inhibiting AKT/mTOR signaling and promoting Bax/Bcl-2-mediated apoptosis, highlighting its potential for therapeutic repurposing as an adjunct treatment-particularly, in breast cancer patients with coexisting depression.
抑郁症状是乳腺癌进展的公认因素；虽然先前的研究已经调查了抗抑郁药在乳腺癌中的作用，但其治疗潜力仍未得到充分和系统的探索。本研究系统评估了六种临床常用抗抑郁药（艾司西酞普兰、阿米替林、氟西汀、帕罗西汀、去甲文拉法辛和度洛西汀）对4T1（小鼠三阴性）和MCF-7（人雌激素受体/人表皮生长因子受体2）乳腺癌细胞的抗肿瘤疗效。结果表明，度洛西汀表现出最强的细胞毒性，在4T1细胞中的IC值为6.94 μM，在MCF-7细胞中的IC值为16.16 μM。虽然不如多西他赛有效，但度洛西汀仍表现出显著的抗增殖、抗迁移和促凋亡作用。在体内，度洛西汀（10 - 30 mg/kg）显著抑制了荷4T1小鼠的肿瘤生长，同时伴有Ki-67表达降低和E-钙黏蛋白增加。此外，度洛西汀显著抑制AKT和mTOR的磷酸化，从而促进自噬激活，LC3表达增加和P62水平降低证明了这一点。此外，度洛西汀在体外和体内均通过上调Bax和下调Bcl-2表达来促进细胞凋亡。这些发现表明，度洛西汀通过抑制AKT/mTOR信号传导和促进Bax/Bcl-2介导的细胞凋亡发挥抗乳腺癌作用，突出了其作为辅助治疗进行治疗性药物重新利用的潜力，特别是在合并抑郁症的乳腺癌患者中。
