Wang Weiqun, Zhang Hongliang, Qu Yikun, Li Yue, Peng Peng, Lu Chengbo, Zhao Xinyue, Cai Ziteng, Peng Chaonan, Guo Xiaoli, Guo Yuxin, Li Jie, Li Xuebin, Jia Linlin, Yang Guangyuan
The Basic Medical College, Jiamusi University, Jiamusi, 154007, Heilongjiang, China.
State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210018, Jiangsu, China.
Sci Rep. 2025 Jul 1;15(1):20987. doi: 10.1038/s41598-025-02125-5.
Inetetamab, a trastuzumab biosimilar, has obtained approval for the treatment of HER2-positive advanced metastatic breast cancer. Despite studies indicating its cardiotoxic properties, the intricate mechanisms underlying its toxicity remain elusive. In the present study, we demonstrated in vitro that exogenous administration of Inetetamab triggered injury in H9c2 myocardial cells, characterized by a significant decrease in cell viability and noticeable morphological changes. Furthermore, exogenous exposure to Inetetamab elicited a series of toxic effects within H9c2 cells, notably promoting apoptosis and autophagy, diminishing the mitochondrial membrane potential (DCm), and elevating intracellular ROS production. Concurrently, there was a notable decrease in intracellular MDA generation, accompanied by disruption of the GSH/GSSG balance. In vivo mouse model, Inetetamab administration prominently induced cardiomyocyte injury, characterized by the pathological change in the myocardial tissue and a marked elevation in serum levels of creatine kinase isoenzyme (CK-MB), brain natriuretic peptide (BNP) and cardiac troponin I (cTnI). Similarly, Inetetamab administration also initiated cardiomyocyte apoptosis and oxidative stress injury in vivo. Furthermore, Inetetamab administration significantly modulated the expression of apoptosis- and autophagy-related proteins both in vivo and in vitro. Our study highlights Inetetamab induces cardiotoxicity by affecting apoptosis, oxidative stress and autophagy.
伊尼妥单抗是一种曲妥珠单抗生物类似药，已获批用于治疗HER2阳性晚期转移性乳腺癌。尽管有研究表明其具有心脏毒性，但毒性背后的复杂机制仍不清楚。在本研究中，我们在体外证明，外源性给予伊尼妥单抗会引发H9c2心肌细胞损伤，其特征是细胞活力显著下降和明显的形态学变化。此外，外源性暴露于伊尼妥单抗会在H9c2细胞内引发一系列毒性作用，特别是促进细胞凋亡和自噬，降低线粒体膜电位（DCm），并提高细胞内活性氧的产生。同时，细胞内丙二醛的生成显著减少，伴随着谷胱甘肽/氧化型谷胱甘肽平衡的破坏。在体内小鼠模型中，给予伊尼妥单抗显著诱导心肌细胞损伤，其特征是心肌组织的病理变化以及血清肌酸激酶同工酶（CK-MB）、脑钠肽（BNP）和心肌肌钙蛋白I（cTnI）水平的显著升高。同样，给予伊尼妥单抗也会在体内引发心肌细胞凋亡和氧化应激损伤。此外，给予伊尼妥单抗在体内和体外均显著调节凋亡和自噬相关蛋白的表达。我们的研究强调伊尼妥单抗通过影响凋亡、氧化应激和自噬来诱导心脏毒性。
