Suppression of Doxorubicin and Hypoxia Induced Mitochondrial Perturbations and Necrotic Cell Death of Ventricular Myocytes by the Polyphenolic Compound Ellagic Acid
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Date
2016
Authors
Afsharinezhad, Pegah
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Abstract
Ellagic acid (EA), is a polyphenolic compound with strong antioxidant properties, however, the effects of EA on cardiac
cell death have not been formally investigated. In this report, we provide new exciting evidence that EA suppressed
mitochondrial perturbations and cell death of cardiac myocytes mediated by the chemotherapy drug doxorubicin (Dox)
or hypoxia (HPX). Cells treated with Dox or subjected to HPX exhibited a marked increase in the inducible death
protein Bcl-2 Nineteen Kilodalton Interacting protein 3 (Bnip3). This coincided with mitochondrial perturbations
including increased reactive oxygen species (ROS), loss of mitochondrial membrane potential, increased mitochondrial
fission and reduced cell viability compared to vehicle treated normoxic control cells. Importantly cardiac myocytes
treated with Dox in the presence of EA were indistinguishable from vehicle treated control cells displaying normal
mitochondrial morphology, reduced ROS, and preserved mitochondrial membrane potential. Interestingly,
mitochondrial targeting of Bnip3 in cells treated with Dox was markedly decreased by EA. This was accompanied by a
concomitant reduction in cardiac cell death and increased cell viability. Hence, the present findings provide the first
direct evidence that EA is sufficient to suppress mitochondrial injury and cell death of cardiac myocytes induced by Dox
and hypoxia by a mechanism that impinges upon the death protein Bnip3. Our exciting data further suggest that by
mitigating the cardiotoxic effects of Dox, adjunctive therapy with EA may provide a therapeutic advantage to cancer
patients undergoing anthracycline treatment.
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Keywords
ellagic acid