Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase

Autor: Cara Beahm, Tammy F. Chu, David Kramer, Thomas Force, Ming-Hui Chen, Kathleen C. Woulfe, Jean-Bernard Durand, Ronald J. Vagnozzi, Risto Kerkelä
Rok vydání: 2010
Předmět:
Indoles
Biopsy
mTORC1
AMP-Activated Protein Kinases
urologic and male genital diseases
Rats
Sprague-Dawley
Mice
AMP-activated protein kinase
Sunitinib
Myocytes
Cardiac
General Pharmacology
Toxicology and Pharmaceutics
Research Articles
Membrane Potential
Mitochondrial
Ventricular Remodeling
General Neuroscience
TOR Serine-Threonine Kinases
General Medicine
female genital diseases and pregnancy complications
Mitochondria
Echocardiography
Signal transduction
Tyrosine kinase
medicine.drug
Signal Transduction
medicine.medical_specialty
Cell Survival
Biology
Mechanistic Target of Rapamycin Complex 1
General Biochemistry
Genetics and Molecular Biology
Inhibitory Concentration 50
Growth factor receptor
Internal medicine
medicine
Animals
Humans
Pyrroles
Protein Kinase Inhibitors
Cardiotoxicity
Myocardium
AMPK
Proteins
Capillaries
Rats
Mice
Inbred C57BL
Endocrinology
Multiprotein Complexes
biology.protein
Cancer research
Transcription Factors
Zdroj: Clinical and translational science. 2(1)
ISSN: 1752-8062
Popis: Tyrosine kinase inhibitors (TKIs) are transforming the treatment of patients with malignancies. One such agent, sunitinib (Sutent, Pfizer, New York, NY, USA), has demonstrated activity against a variety of solid tumors. Sunitinib is “multitargeted,” inhibiting growth factor receptors that regulate both tumor angiogenesis and tumor cell survival. However, cardiac dysfunction has been associated with its use. Identification of the target of sunitinib‐associated cardiac dysfunction could guide future drug design to reduce toxicity while preserving anticancer activity. Herein we identify severe mitochondrial structural abnormalities in the heart of a patient with sunitinib‐induced heart failure. In cultured cardiomyocytes, sunitinib induces loss of mitochondrial membrane potential and energy rundown. Despite the latter, 5′ adenosine monophosphate‐activated protein kinase (AMPK) activity, which should be increased in the setting of energy compromise, is reduced in hearts of sunitinib‐treated mice and cardiomyocytes in culture, and this is due to direct inhibition of AMPK by sunitinib. Critically, we find that adenovirus‐mediated gene transfer of an activated mutant of AMPK reduces sunitinib‐induced cell death. Our findings suggest AMPK inhibition plays a central role in sunitinib cardiomyocyte toxicity, highlighting the potential of off‐target effects of TKIs contributing to cardiotoxicity. While multitargeting can enhance tumor cell killing, this must be balanced against the potential increased risk of cardiac dysfunction.
Databáze: OpenAIRE
Externí odkaz: