School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550025, China.
Biomed Pharmacother. 2024 Apr;173:116353. doi: 10.1016/j.biopha.2024.116353. Epub 2024 Mar 2.
Peiminine, the primary biologically active compound from Fritillaria thunbergii Miq., has demonstrated significant pharmacological activities. Doxorubicin is one of the most potent chemotherapeutic agents for breast cancer (BC). This study was designed to investigate the efficacy and underlying mechanisms of Peiminine combined with Doxorubicin in treating BC. Our results demonstrated that the combination of Peiminine and 1 mg/kg Doxorubicin exhibited more significant suppression of tumor growth compared with the monotherapy in MDA-MB-231 xenograft nude mice model, which is comparable to the effect of 3 mg/kg Doxorubicin in vivo. Notably, the 3 mg/kg Doxorubicin monotherapy resulted in organ toxicity, specifically in the liver and heart, whereas no toxicity was observed in the combination group. In vitro, this combined treatment exhibited a synergistic reduction on the viability of BC cells. Peiminine enhanced the cell cycle arrest and DNA damage induced by Doxorubicin. Furthermore, the combination treatment effectively blocked DNA repair by inhibiting the MAPKs signaling pathways. And ZEB1 knockdown attenuated the combined effect of Peiminine and Doxorubicin on cell viability and DNA damage. In conclusion, our study found that the combination of Peiminine and Doxorubicin showed synergistic inhibitory effects on BC both in vivo and in vitro through enhancing Doxorubicin-induced DNA damage. These findings support that their combination is a novel and promising therapeutic strategy for treating BC.
冬凌草甲素是来自贝母属植物的主要生物活性化合物，具有显著的药理活性。多柔比星是治疗乳腺癌（BC）最有效的化疗药物之一。本研究旨在探讨冬凌草甲素联合多柔比星治疗 BC 的疗效及其作用机制。我们的研究结果表明，冬凌草甲素与 1mg/kg 多柔比星联合用药在 MDA-MB-231 异种移植裸鼠模型中比单药治疗更显著地抑制肿瘤生长，其效果与体内 3mg/kg 多柔比星相当。值得注意的是，3mg/kg 多柔比星单药治疗导致了器官毒性，特别是在肝脏和心脏，而联合治疗组未观察到毒性。在体外，这种联合治疗对 BC 细胞的活力表现出协同抑制作用。冬凌草甲素增强了多柔比星诱导的细胞周期停滞和 DNA 损伤。此外，联合治疗通过抑制 MAPKs 信号通路有效地阻断了 DNA 修复。ZEB1 敲低减弱了冬凌草甲素和多柔比星联合处理对细胞活力和 DNA 损伤的协同作用。总之，我们的研究发现，冬凌草甲素和多柔比星联合应用在体内和体外均表现出对 BC 的协同抑制作用，通过增强多柔比星诱导的 DNA 损伤。这些发现支持它们的联合应用是治疗 BC 的一种新的有前途的治疗策略。
