15 Mitochondrial Division Inhibitor-1 Protects against Doxorubicin-Induced Cardiotoxicity

Abstract

Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia-reperfusion injury (IRI), we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in nai and stressed conditions. Drug-induced effects were assessed using the Langendorff system, oxidative stress model using isolated cardiomyocytes, western blot and flow cytometry analysis to measure the levels of p-Akt, p-Erk ½, p-Drp1 and p-p53 upon drug-treatment. The HL60 leukaemia cell line was used to evaluate the effects of combined treatment of doxorubicin and mdivi-1 on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk-ratio in both nai and IRI conditions. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were prevented with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury. We have identified for the first time mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties.