Original ContributionResveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway
Section snippets
Material and methods
DOX, RV, and nicotinamide (NIC) were purchased from Sigma Chemical Co. (St. Louis, MO, USA). Carboxy-H2DCFDA and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) were purchased from Molecular Probes (Eugene, OR, USA). MnSOD and acetyl histone H3 antibodies were purchased from Upstate Cell Signaling (Lake Placid, NY, USA), and the α-actinin and α-tubulin antibodies (loading controls) were obtained from Sigma.
DOX-induced mitochondrial ROS production is inhibited by pretreatment with RV
DOX has been reported to cause an increase in cellular ROS production [21], [51]. However, with DOX localization in the mitochondria, we hypothesized that DOX would specifically increase mitochondrial ROS production. Mitochondria were stained with MitoTracker Deep Red and ROS production was monitored by oxidation of carboxy-H2DCFDA, a widely used ROS marker. NRVM treated with 50 μM DOX for 10 min induced a significant increase in ROS production specifically in the mitochondria compared to
Discussion
DOX-induced cardiotoxic side effects, specifically cardiomyocyte death and development of heart failure, remain a concern for long-term care of cancer survivors and thus are an area of intense research. However, the specific mechanism is unknown, but thought to involve oxidative stress. Other studies have reported an increase in cellular ROS production in H9c2 cells in response to DOX; however, our results show that the increase in ROS production is localized to the mitochondria in NRVM and
Acknowledgments
This work was supported by the American Cancer Society (R.S.K.) and an American Heart Association Scientist Development Grant (R.S.K.). We thank the AMC Imaging Core and Dr. Joseph Mazurkiewicz for consultation on imaging and linear unmixing and Camille Minnery and Kofi Asante for isolation of cardiomyocytes. We also thank Dr. J. Andre Melendez for his help with manuscript revisions.
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