Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis.
Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.
Wallace
Kendall B
KB
Department of Biochemistry & Molecular Biology, University of Minnesota School of Medicine, Duluth, MN 55812, USA. kwallace@d.umn.edu
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D002118:Calcium