Abstract
Purpose
Cardiotoxic side effects of anthracyclines limit their use as effective chemotherapeutics. One mechanistic model of anthracycline-induced cardiotoxicity is attributed to the generation of intracellular reactive oxygen species (ROS). However, this theory has been questioned because several cardioprotective strategies have included the use of antioxidants without significant clinical benefit. We sought to determine whether measurement of intracellular reactive oxygen species after anthracycline exposure in vivo and in vitro could provide a means for designing more effective antioxidant-based cardioprotective schemes.
Methods
Intracellular levels of ROS were assessed in peripheral blood mononuclear cells from leukemia bearing mice exposed to anthracyclines and in patients receiving anthracyclines. Comparison of cell death induction and ROS levels were also conducted in vitro in cardiomyocyte and leukemia lines. ROS blockade using antioxidants was conducted, and effects on cell death were assessed.
Results
Elevated ROS in blood of mice and representative patient samples correlated with cardiomyocyte necrosis and decreased ejection fraction. In vitro, comparison of the cytotoxic effects of anthracyclines in acute leukemia cells and in cardiomyocytes revealed distinct kinetics of cell death induction and dependence upon oxidative stress. Although apoptotic cell death was observed in both acute leukemia cells and cardiomyocytes, the antioxidant N-acetylcysteine protected cardiomyocytes but not acute leukemia cells from anthracycline cytotoxicity.
Conclusions
Our findings point toward revisiting the use of NAC as a cardioprotective agent since it does not appear to interfere with the cytotoxic action of anthracyclines. NAC has been evaluated clinically for cardioprotective activity but future trials must ensure that adequate dose, scheduling and incorporation of markers of oxidative stress are included.
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Funding
This study was supported by a research grant from Riders for the Cure, and a gift from David Herr & Family. J.F. and D.E. were supported by Division of Pediatrics funding for the Pediatric Hematology and Oncology Fellowship. Funding to J.C. from the NIH/NCI RO1 CA115811 is gratefully acknowledged. This work was also supported by the NIH/NCI under Award Number P30CA016672 and used the Research Animal Core Facility.
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J.C. has received research support from Celgene and Nereus Pharmaceuticals.
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Joy Marie Fulbright and Daniela E. Egas-Bejar have equal contribution to the manuscript.
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Fulbright, J.M., Egas-Bejar, D.E., Huh, W.W. et al. Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy. Cancer Chemother Pharmacol 76, 1297–1307 (2015). https://doi.org/10.1007/s00280-015-2879-4
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DOI: https://doi.org/10.1007/s00280-015-2879-4