Abstract
The anticancer tyrosine kinase inhibitor sunitinib has been shown recently to be cardiotoxic. Using a neonatal rat myocyte model, we investigated various mechanisms that might be responsible for its cardiotoxicity. Sunitinib potently inhibited the enzyme activity of both AMP-activated protein kinase (AMPK) and the ribosomal S6 kinase RSK1 at therapeutically relevant concentrations. Heart tissue with its high energy needs might be particularly sensitive to inhibition of AMPK because of its role as an energy sensor regulating ATP levels. As measured by lactate dehydrogenase release, sunitinib treatment of myocytes caused dose-dependent damage at therapeutic levels. Sunitinib treatment also caused a dose-dependent reduction in myocyte protein levels of the phosphorylated α and β isoforms of the AMPK phosphorylation target acetyl-Coenzyme A carboxylase. However, myocytes were not protected from sunitinib treatment by pretreating them with the AMPK-activating antidiabetic drug metformin. Sunitinib treatment of myocytes also did not affect cellular ATP levels. Together, these last two results do not suggest a major role for inhibition of AMPK in sunitinib-induced myocyte damage. Dexrazoxane, which is a clinically approved doxorubicin cardioprotective agent, also did not protect myocytes from damage, which suggests that sunitinib did not induce oxidative damage. In conclusion, even though sunitinib potently inhibits AMPK and RSK1, given the extreme lack of kinase selectivity that sunitinib exhibits, it is likely that inhibition of other kinases or combinations of kinases are responsible for the cardiotoxic effects of sunitinib.
Footnotes
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This work was supported by the Canadian Institutes of Health Research, the Canada Research Chairs program, and a Canada Research Chair in Drug Development (to B.B.H.), and by a postdoctoral fellowship (to K.A.O.) from the Manitoba Health Research Council.
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ABBREVIATIONS: AMPK, AMP-activated protein kinase; ACC, acetyl-Coenzyme A carboxylase; DF-x, Dulbecco's modified Eagle's medium/Ham's F-12 medium, 1:1 where x is the percentage (v/v) of serum; LDH, lactate dehydrogenase; RSK, ribosomal S6 kinase; DCF, 2′,7′-dichlorofluorescin; ICRF-187, dexrazoxane.
- Received June 30, 2008.
- Accepted September 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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