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ToxSci Advance Access published online on July 29, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn157
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Effect of the Multi-targeted Tyrosine Kinase Inhibitors Imatinib, Dasatinib, Sunitinib and Sorafenib on Mitochondrial Function in Isolated Rat Heart Mitochondria and H9c2 cells

Yvonne Will*, James A. Dykens{dagger}, Sashi Nadanaciva{ddagger}, Brad Hirakawa{dagger}, Joseph Jamieson{dagger}, Lisa D. Marroquin{dagger}, James Hynes§, Shem Patyna and Bart A. Jessen{dagger},1

* Exploratory Safety Differentiation, Pfizer, Inc., Eastern Point Rd, Groton, CT 06340 {dagger} Drug Safety Research and Development, Pfizer, Inc., 10646 Science Center Drive, San Diego, CA 92121 {ddagger} MitoSciences, Inc., 1850 Millrace Drive, Eugene, OR 97403 § Luxcel Biosciences Ltd., Lee Maltings, Cork, Ireland Clinical Development Pfizer Inc, 10646 Science Center Drive, San Diego, CA 92121

1 To whom correspondence should be addressed., Fax: (858)678 8290, Phone: (858) 622-6039, E-mail: Bart.Jessen{at}pfizer.com

Received June 3, 2008; revision received July 18, 2008; accepted July 21, 2008


  Abstract

Cardiovascular disease has recently been suggested to be a significant complication of cancer treatment with several kinase inhibitors. In some cases, the mechanisms leading to cardiotoxicity are postulated to include mitochondrial dysfunction, either as a primary or secondary effect. Detecting direct effects on mitochondrial function, such as uncoupling of OXPHOS or inhibition of electron transport chain components, as well as identifying targets within the mitochondrial electron transport chain, can be accomplished in vitro. Here, we examined the effects of the tyrosine kinase inhibitor drugs imatinib, dasatinib, sunitinib, and sorafenib on ATP content in H9c2 cells grown under conditions where cells are either glycolytically or aerobically poised. Furthermore, we measured respiratory capacity of isolated rat heart mitochondria in the presence of the four kinase inhibitors and examined their effect on each of the oxidative phosphorylation complexes. Of the four kinase inhibitors examined, only sorafenib directly impaired mitochondrial function at clinically relevant concentrations, potentially contributing to the cytotoxic effect of the drug. For the other three kinase inhibitors lacking direct mitochondrial effects, altered kinase and other signaling pathways, are a more reasonable explanation for potential toxicity.


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