Adriamycin-induced oxidative mitochondrial cardiotoxicity |
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Authors: | J M Berthiaume K B Wallace |
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Institution: | (1) Toxicology Graduate Program, Medical School, University of Minnesota, Duluth, Minnesota, USA;(2) 255 Medical School, University of Minnesota, 1035 University Drive, Duluth, MN 55812, USA |
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Abstract: | The anticancer agent Adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity. Numerous studies
have attempted to characterize and elucidate the mechanism(s) behind its cardiotoxic effect. Despite a wealth of data covering
a wide-range of effects mediated by the drug, the definitive mechanism remains a matter of debate. However, there is consensus
that this toxicity is related to the induction of reactive oxygen species (ROS). Induction of ROS in the heart by ADR occurs
via redox cycling of the drug at complex I of the electron transport chain. Many studies support the theory that mitochondria
are a primary target of ADR-induced oxidative stress, both acutely and long-term. This review focuses on the effects of ADR
redox cycling on the mitochondrion, which support the hypothesis that these organelles are indeed a major factor in ADR cardiotoxicity.
This review has been constructed with particular emphasis on studies utilizing cardiac models with clinically relevant doses
or concentrations of ADR in the hope of advancing our understanding of the mechanisms of ADR toxicity. This compilation of
current data may reveal valuable insights for the development of therapeutic strategies better tailored to minimizing the
dose-limiting effect of ADR. |
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Keywords: | Adriamycin doxorubicin mitochondria reactive oxygen species cardiac mtDNA |
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