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1 Department of Pediatrics, Wayne State University, Detroit, Michigan, USA
2 Department of Pathology, Wayne State University, Detroit, Michigan, USA
3 Department of Pathology, Wayne State University, Detroit, Michigan, USA; Department of Pathology, John D. Dingell Department of Veterans Affairs Medical Center, Detroit, Michigan, USA
* To whom correspondence should be addressed. E-mail: thlecuye{at}med.wayne.edu.
Anthracyclines (AC) are anti-tumor antibiotics with significant activity against solid and hematologic malignancies. One problem preventing more widespread use has been the development of cardiac toxicity. Experimental evidence supports oxidant stress as an important trigger and/or mediator of AC-induced cardiotoxicity (ACT). Therefore, reducing oxidant stress should be protective against ACT. To determine whether antioxidant protein overexpression can reduce ACT, we developed a cell culture model system using the H9C2 cardiac cell line exhibiting controlled overexpression of the a4 isoform of glutathione transferase (GST). Treatment with the AC doxorubicin (DOX) produced both oncosis, manifested by an increase in the number of cells staining positive for trypan blue, and apoptosis, indicated by the presence of positive deoxynucleotidyl transferase (TUNEL) staining. In both cases, the loss of cell viability was preceded by an AC-induced increase in fluorescence with carboxy-dichlorofluorescein diacetate (DFDA), demonstrating the presence of high levels of reactive oxygen species (ROS). The DOX-induced increase in ROS was reduced to control levels by maximal GSToverexpression. Coincident with this elimination of oxidative stress, there was a reduction in both trypan-blue and TUNEL-positive cells, indicating that GST overexpression reduced both ROS and cell death in this model system. We conclude that GST overexpression may be an important part of a protective strategy against ACT and that this model system will aid in defining steps in the pathway(s) leading to AC-induced cell death that can be therapeutically manipulated.
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