Bevacizumab as a monoclonal antibody inhibits mitochondrial complex II in isolated rat heart mitochondria: ameliorative effect of ellagic acid

Drug-induced cardiotoxicity usually manifests as heart failure or left ventricular systolic dysfunction. Left ventricular dysfunction is a rarely reported side effect of bevacizumab (BEV) with an incidence of 1.2%, and this occurs irrespective of the route of administration. In this study, we focused on an analysis of BEV effects on mitochondrial complexes activities and protective effect of ellagic acid (EA) against BEV-induced mitochondria toxicity. Rat heart mitochondria were isolated using differential centrifugation form wistar rats. Using biochemical and flowcytometry assays we evaluated mitochondrial complexes activity, succinate dehydrogenases (SDH), mitochondrial swelling, reactive oxygen species (ROS) formation and mitochondrial membrane potential (MMP) in isolated mitochondria. We observed only decreased activity of complexes II after exposure with BEV (50 and 100 mu g/ml). The inhibition of complex II is paralleled by the decreased MMP, mitochondrial swelling, and ROS formation. Also, we showed that EA (10-100 mu M) as an antioxidant and natural agent significantly decreases mitochondrial toxicity induced by BEV. Together, for the first time, this preliminary study has demonstrated a significant decrease in activity of complexes II after exposure with BEV and proved the protective effects of EA in alleviating BEV-mediated mitochondria toxicity.

Automated summary

This study found that BEV exposure decreased the activity of mitochondrial complex II, leading to decreased mitochondrial membrane potential, mitochondrial swelling, and ROS formation. Additionally, it demonstrated that EA as an antioxidant could significantly alleviate BEV-induced mitochondrial toxicity.