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 µg/ml). The inhibition of complex II is paralleled by the decreased MMP, mitochondrial swelling, and ROS formation. Also, we showed that EA (10-100 µM) 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.

Curcumin attenuates bevacizumab-induced toxicity via suppressing oxidative stress and preventing mitochondrial dysfunction in heart mitochondria.

Heart failure was subsequently noted in 2-4% of patients on bevacizumab (BEV). Whereas mitochondria play an important role in myocardial tissue homeostasis, deterioration in mitochondrial function will eventually lead to cardiomyocyte cell death and consequently cardiovascular dysfunction. Therefore, the aim of our study is to search the effects of BEV on isolated rat heart mitochondria and cardiomyocytes, and survey the effect of curcumin as a mitochondrial protective and cardioprotective agent. Rat heart mitochondria and cardiomyocytes were isolated from adult rat heart ventricular. By using biochemical and flow cytometry evaluations, the parameters of mitochondrial toxicity including succinate dehydrogenase (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse, reactive oxygen species (ROS) formation and lipid peroxidation (LP), and cellular assays such as cytotoxicity and MMP collapse were evaluated. Results revealed that BEV (up to 50 µg/ml) induced a concentration- and time-dependent rise in mitochondrial ROS formation, MMP collapse, mitochondrial swelling, LP, and inhibition of SDH in rat heart mitochondria. Our results showed that curcumin (10-100 µM) significantly ameliorated BEV-induced mitochondrial toxicities. Also, our results in cellular assays confirmed amelioration effect of curcumin against BEV toxicity. These results indicate that the cardiotoxic effects of BEV are associated with mitochondrial dysfunction and ROS formation, which finally ends in MMP collapse and mitochondrial swelling as the "point of no return" in the cascade of events leading to apoptosis. Also, results of this study suggest that probably the combination therapy of BEV and curcumin could decrease mitochondrial effects of this drug.

Repeated Administration of Mercury Intensifies Brain Damage in Multiple Sclerosis through Mitochondrial Dysfunction.

In this study we investigated the additive effect of mercury on the brain mitochondrial dysfunction in experimental autoimmune encephalomyelitis (EAE) model. Experimental animals (female C57BL/6 mice) are divided into four groups (n = 8); control, Hg, EAE, EAE with Hg. EAE model of MS induced by injecting myelin oligodendrocyte glycoprotein (MOG). Neurobehavioral alterations are recorded and then mice were sacrificed at day 28 and brain mitochondria were isolated and mitochondrial toxicity parameters including mitochondrial swelling, reactive oxygen species (ROS) formation, collapse of mitochondrial membrane potential (MMP) and cytochrome c release were measured. Our results showed that repeated treatment of mercury following induction of EAE in mice significantly increased the neurobehavioral scores, as well as mitochondrial toxicity through ROS formation, mitochondrial swelling, collapse of MMP and cytochrome c release. Our findings proved that repeated exposure with mercury accelerates progression of MS through mitochondrial damage related to oxidative stress and finally apoptosis.