Bevacizumab-Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

The molecular mechanisms underlying the cardiotoxicity associated with bevacizumab, a first-line immunotherapeutic agent used to treat lung cancer, are not fully understood. Here, we examined intracellular signal transduction in cardiomyocytes after exposure to different doses of bevacizumab in vitro. Our results demonstrated that bevacizumab significantly and dose-dependently reduces cardiomyocyte viability and increases cell apoptosis. Bevacizumab treatment also led to mitochondrial dysfunction in cardiomyocytes, as evidenced by the decreased ATP production, increased ROS production, attenuated antioxidative enzyme levels, and reduced respiratory complex function. In addition, bevacizumab induced intracellular calcium overload, ER stress, and caspase-12 activation. Finally, bevacizumab treatment inhibited the ERK signaling pathway, which, in turn, significantly reduced cardiomyocyte viability and contributed to mitochondrial dysfunction. Together, our results demonstrate that bevacizumab-mediated cardiotoxicity is associated with mitochondrial dysfunction, ER stress, and ERK pathway inactivation. These findings may provide potential treatment targets to attenuate myocardial injury during lung cancer immunotherapy.