Research Article: Attenuation of Doxorubicin-Induced Cardiotoxicity by mdivi-1: A Mitochondrial Division/Mitophagy Inhibitor

Date Published: October 17, 2013

Publisher: Public Library of Science

Author(s): Mayel Gharanei, Afthab Hussain, Omar Janneh, Helen Maddock, Partha Mukhopadhyay.


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 and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division 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 naïve conditions and during ischaemia/reperfusion injury. 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 reversed 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 HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties.

Partial Text

The anthracycline antibiotic doxorubicin is used to treat a wide variety of cancers, but reports of its cardiotoxic properties compromises its clinical utility [1–3]. The cardiotoxic effects of doxorubicin are thought to be mediated via disruption of the mitochondrial function [4]. Previous studies have also shown doxorubicin to cause cardiotoxicity through the generation of free radicals [5], stimulation of lipid peroxidation [6] and alteration and disruption of cellular membrane integrity [7]. Arrhythmias, hypotension and depression of the contractile function are some of the acute effects of doxorubicin-induced cardiotoxicity [8], while chronic heart failure and dilative cardiomyopathy are more common and severe in patients who are on long term anthracyclines treatment [9,10]. Large scale clinical trials have shown that doxorubicin induced cardiotoxicity is irreversible and dose dependent [11].

Doxorubicin treatment is known to cause cardiovascular toxicity due to the generation of reactive oxygen species [5] and calcium overload [33]. Previous research has demonstrated that doxorubicin induced toxicity affects mitochondrial bioenergetics and causes mitochondrial fragmentation [17]. We demonstrate that doxorubicin induced dysfunction on the haemodynamic parameters of the hearts are reversed by mdivi-1, a relatively specific inhibitor of mitochondrial division.