New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics.
Cardiotoxic side-effects represent a serious complication of anticancer therapy with anthracyclines, in particular with doxorubicin (DXR) being the leading drug of the group. Different hypotheses, accentuating various mechanisms and/or targets, have been proposed to explain DXR-induced cardiotoxicity. This review focuses on the myocardial energetic network as a target of DXR toxic action in heart and highlights the recent advances in understanding its role in development of the DXR related cardiac dysfunction. We present a survey of DXR-induced defects in different steps of cardiac energy metabolism, including reduction of oxidative capacity of mitochondria, changes in the profile of energy substrate utilization, disturbance of energy transfer between sites of energy production and consumption, as well as defects in energy signaling. Considering the wide spectrum and diversity of the changes reported, we attempt to integrate these facts into a common framework and to discuss important functional and temporal relationships between DXR-induced events and the possible underlying molecular mechanisms.
Tokarska-Schlattner
Malgorzata
M
Institute of Cell Biology, ETH Zurich, Hönggerberg HPM D24, CH-8093 Zürich, Switzerland. malgorzata.tokarska@cell.biol.ethz.ch
Zaugg
Michael
M
Zuppinger
Christian
C
Wallimann
Theo
T
Schlattner
Uwe
U
D055372:AMP-Activated Protein Kinases; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects*; D006019:Glycolysis; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010710:Phosphates / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D009097:Multienzyme Complexes; D010710:Phosphates; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D003402:Creatine Kinase