Objective: To investigate the effect of Kaixinsan (KXS, a traditional Chinese medicine formula) for alleviating adriamycin-induced depression-like behaviors in mice bearing breast cancer xenografts and explore the pharmacological mechanism.
Methods: Forty female BALB/c mice were randomized equally into control group, model group, and low- and high-dose KXS treatment groups, and in the latter 3 groups, mouse models bearing orthotopic breast cancer 4T1 cell xenografts were established and treated with adriamycin along with saline or KXS via gavage. Depression-like behaviors of the mice were assessed using open field test and elevated plus-maze test, and the changes in serum levels of depression-related factors were examined. RNA-seq analysis and transmission electron microscopy were used and ferroptosis-related factors were detected to explore the mechanisms of adriamycin-induced depression and the therapeutic mechanism of KXS. The results were verified in SH-SY5Y cells using ferroptosis inhibitor Fer-1 as the positive control.
Results: KXS significantly alleviated depression-like behaviors and depression-related serological changes induced by adriamycin in the mouse models. RNA-seq results suggested that KXS alleviated chemotherapy-induced depression by regulating oxidative stress, lipid metabolism and iron ion binding in the prefrontal cortex. Pathological analysis and detection of ferroptosis-related factors showed that KXS significantly reduced ferroptosis in the prefrontal cortex of adriamycin-treated mice. In SH-SY5Y cells, both KXS-medicated serum and the ferroptosis inhibitor were capable of attenuating adriamycin-induced cell ferroptosis.
Conclusion: KXS alleviates adriamycininduced depression-like behaviors in mice by reducing ferroptosis in the prefrontal cortex of breast cancer-bearing mice.
目的: 明确中药复方开心散缓解乳腺癌阿霉素化疗性抑郁的疗效，并分析其药理机制。
方法: 将40只雌性BALB/c小鼠通过原位注射4T1细胞建立乳腺癌小鼠模型，将小鼠随机分为对照组、模型组、开心散低剂量组和开心散高剂量组，10只/组。通过旷场试验和高架十字迷宫实验行为学分析、抑郁相关因子血清学检测、转录组学分析、透射电镜病理分析和铁死亡相关因子检测分析阿霉素诱导的化疗性抑郁产生的病因以及开心散的作用机制。利用SH-SY5Y细胞系构建体外模型并使用铁死亡抑制剂Fer-1进行阳性对照，验证动物实验结果。
结果: 开心散显著逆转阿霉素化疗所致的抑郁样行为（P<0.001）、逆转抑郁相关血清学的改变（P<0.05）；转录组学结果显示，开心散缓解化疗性抑郁与调控前额叶皮质组织氧化应激、脂质代谢和铁离子结合等过程有关；病理学分析、铁死亡相关因子检测结果显示，开心散能减轻阿霉素化疗所致的前额叶皮质组织铁死亡（P<0.01）。体外实验结果也显示，开心散含药血清和铁死亡抑制剂均能逆转阿霉素诱导的神经细胞铁死亡（P<0.001）。
结论: 开心散通过减轻乳腺癌阿霉素化疗所致的大脑前额叶皮质组织铁死亡，进而缓解化疗性抑郁。
Keywords: Kaixinsan; breast cancer; chemotherapy; depression; ferroptosis.