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Cardiovascular Toxicology

Erschienen in:

01.03.2010

Mechanisms of Myocyte Cytotoxicity Induced by the Multikinase Inhibitor Sorafenib

verfasst von: Brian B. Hasinoff, Daywin Patel

Erschienen in: Cardiovascular Toxicology | Ausgabe 1/2010

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Abstract

The use of the anticancer multikinase inhibitor sorafenib is associated with cardiac ischemia or infarction and an increase in hypertension. We investigated various mechanisms that might be responsible for its cardiotoxicity in a neonatal rat myocyte model. As measured by lactate dehydrogenase release, sorafenib treatment of myocytes caused dose-dependent damage at therapeutically relevant concentrations. It had been hypothesized that inhibition of RAF1 and BRAF kinases may be responsible for sorafenib-induced cardiotoxicity. However, because sorafenib treatment did not inhibit phosphorylation of ERK (extracellular signal-regulated kinase), it was concluded that sorafenib did not exert its damaging effects through RAF inhibition of the RAF/MEK/ERK kinase cascade. The clinically approved doxorubicin cardioprotective agent dexrazoxane did not protect myocytes from damage. At lower sorafenib concentrations, at least, these results are consistent with sorafenib not being able to induce significant oxidative damage. In conclusion, given the extreme lack of kinase selectivity that sorafenib exhibits, it is likely that inhibition of kinases other than RAF, or combinations of kinases, contributes to the cardiotoxic effects of sorafenib.

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Titel: Mechanisms of Myocyte Cytotoxicity Induced by the Multikinase Inhibitor Sorafenib
verfasst von: Brian B. Hasinoff
Daywin Patel
Publikationsdatum: 01.03.2010
Verlag: Humana Press Inc
Erschienen in: Cardiovascular Toxicology / Ausgabe 1/2010
Print ISSN: 1530-7905
Elektronische ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-009-9056-0

Springer Medizin

Abstract

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