Wei Shanshan, Ma Wanjun, Xie Suifen, Liu Sa, Xie Ning, Li Wenqun, Zhang Bikui, Liu Jian
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China.
Cardiovasc Drugs Ther. 2023 Nov 9. doi: 10.1007/s10557-023-07522-4.
Trastuzumab is a landmark agent in the treatment of human epidermal growth factor receptor-2(HER2)-positive breast cancer. Nevertheless, trastuzumab also comes with unexpected cardiac side effects. Hyperoside is a natural product that serves beneficial roles in cardiovascular disease. This study aimed to explore the effect and mechanism of hyperoside in trastuzumab-induced cardiotoxicity.
A female C57BL/6 mice cardiotoxicity model was established via intraperitoneally injecting with trastuzumab (10 mg/kg/day, once every other day, cumulative dosage to 40 mg/kg) with or without hyperoside (15 or 30 mg/kg/day) administration. In vitro, the H9c2 cells were exposed to 1 μM trastuzumab with or without hyperoside (100 or 200 μM) administration. Cardiac function was evaluated by echocardiographic, myocardial enzymes levels, and pathological section examinations. TUNEL staining and Annexin V-FITC/ propidium iodide flow cytometry were used to analyze the cardiomyocyte apoptosis.
Compared to the control group, the LVEF, LVFS was decreased and the concentrations of cTnT, CK, CK-MB and LDH in mice were significantly increased after treatment with trastuzumab. Collagen deposition and cardiomyocyte hypertrophy were observed in the myocardium of the trastuzumab group. However, these changes were all reversed by different doses of hyperoside. In addition, hyperoside attenuated trastuzumab-induced myocardium apoptosis and H9c2 cells apoptosis through inhibiting the expressions of cleaved caspase-3 and Bax. Trastuzumab abolished the PI3K/Akt signaling pathway in mice and H9c2 cells, while co-treatment of hyperoside effectively increased the ratio of p-Akt/Akt.
Hyperoside inhibited trastuzumab-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Hyperoside may be a promising therapeutic approach to trastuzumab-induced cardiotoxicity.
曲妥珠单抗是治疗人表皮生长因子受体2（HER2）阳性乳腺癌的标志性药物。然而，曲妥珠单抗也伴有意想不到的心脏副作用。金丝桃苷是一种在心血管疾病中发挥有益作用的天然产物。本研究旨在探讨金丝桃苷在曲妥珠单抗诱导的心脏毒性中的作用及机制。
通过腹腔注射曲妥珠单抗（10mg/kg/天，隔日一次，累积剂量至40mg/kg）建立雌性C57BL/6小鼠心脏毒性模型，同时给予或不给予金丝桃苷（15或30mg/kg/天）。体外实验中，将H9c2细胞暴露于1μM曲妥珠单抗，同时给予或不给予金丝桃苷（100或200μM）。通过超声心动图、心肌酶水平和病理切片检查评估心脏功能。采用TUNEL染色和Annexin V-FITC/碘化丙啶流式细胞术分析心肌细胞凋亡。
与对照组相比，曲妥珠单抗治疗后小鼠的左室射血分数（LVEF）、左室短轴缩短率（LVFS）降低，心肌肌钙蛋白T（cTnT）、肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）和乳酸脱氢酶（LDH）浓度显著升高。曲妥珠单抗组心肌出现胶原沉积和心肌细胞肥大。然而，不同剂量的金丝桃苷均可逆转这些变化。此外，金丝桃苷通过抑制裂解的半胱天冬酶-3（cleaved caspase-3）和Bax的表达，减轻曲妥珠单抗诱导的心肌细胞凋亡和H9c2细胞凋亡。曲妥珠单抗使小鼠和H9c2细胞中的PI3K/Akt信号通路失活，而金丝桃苷联合治疗可有效提高磷酸化Akt（p-Akt）与Akt的比值。
金丝桃苷通过激活PI3K/Akt信号通路抑制曲妥珠单抗诱导的心脏毒性。金丝桃苷可能是治疗曲妥珠单抗诱导的心脏毒性的一种有前景的治疗方法。
