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This Article Full Text Full Text (PDF) All Versions of this Article: 289/1/H37    most recent 01057.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Tokarska-Schlattner, M. Articles by Schlattner, U. Search for Related Content PubMed PubMed Citation Articles by Tokarska-Schlattner, M. Articles by Schlattner, U.

Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply

¹Institute of Cell Biology, Swiss Federal Institute of Technology, ²Institute of Pharmacology and Toxicology, University of Zürich, and ³Institute of Anesthesiology, University Hospital of Zürich, Zürich, Switzerland

Submitted 14 October 2004 ; accepted in final form 5 March 2005

Doxorubicin (DXR) is a widely used and efficient anticancer drug. However, its application is limited by the risk of severe cardiotoxicity. Impairment of cardiac high-energy phosphate homeostasis is an important manifestation of both acute and chronic DXR cardiotoxic action. Using the Langendorff model of the perfused rat heart, we characterized the acute effects of 1-h perfusion with 2 or 20 µM DXR on two key kinases in cardiac energy metabolism, creatine kinase (CK) and AMP-activated protein kinase (AMPK), and related them to functional responses of the perfused heart and structural integrity of the contractile apparatus as well as drug accumulation in cardiomyocytes. DXR-induced changes in CK were dependent on the isoenzyme, with a shift in protein levels of cytosolic isoenzymes from muscle-type CK to brain-type CK, and a destabilization of octamers of the mitochondrial isoenzyme (sarcometric mitochondiral CK) accompanied by drug accumulation in mitochondria. Interestingly, DXR rapidly reduced the protein level and phosphorylation of AMPK as well as phosphorylation of its target, acetyl-CoA-carboxylase. AMPK was strongly affected already at 2 µM DXR, even before substantial cardiac dysfunction occurred. Impairment of CK isoenzymes was mostly moderate but became significant at 20 µM DXR. Only at 2 µM DXR did upregulation of brain-type CK compensate for inactivation of other isoenzymes. These results suggest that an impairment of kinase systems regulating cellular energy homeostasis is involved in the development of DXR cardiotoxicity.

creatine kinase; adenosine 5'-monophosphate-activated protein kinase; anthracyclines; cardiac energetics; cardiotoxicity

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