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15 Mitochondrial Division Inhibitor-1 Protects against Doxorubicin-Induced Cardiotoxicity
  1. M Gharanei1,
  2. A Hussain1,
  3. O Janneh2,
  4. H L Maddock1
  1. 1Department of Biomolecular and Sport Sciences, Coventry University, Coventry, UK
  2. 2Division of Biomedical Sciences, St. George’s, University of London, London, UK

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 naï 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 naï 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.

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