Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes.
BJU Int
; 110(10): 1455-62, 2012 Nov.
Article
em En
| MEDLINE
| ID: mdl-22508007
ABSTRACT
OBJECTIVES:
To examine the acute effects of sunitinib on inotropic function, intracellular Ca(2+) transients, myofilament Ca(2+) sensitivity and generation of reactive oxygen species (ROS) in human multicellular myocardium and isolated mouse cardiomyocytes. To search for microRNAs as suitable biomarkers for indicating toxic cardiac effects. PATIENTS ANDMETHODS:
After exposure to sunitinib (0.1-10 µg/mL) developed force, diastolic tension and kinetic variables were assessed in isolated human myocardium. Changes in myocyte sarcomere length, whole-cell calcium transients, myofilament force-Ca(2+) relationship, and ROS generation were examined in isolated ventricular mouse cardiomyocytes. Microarray and realtime-PCR were used to screen for differentially expressed microRNAs in cultured cardiomyocytes that were exposed for 24 h to sunitinib.RESULTS:
We found that higher concentrations of sunitinib (1 and 10 µg/mL) decreased developed force at 30 minutes 76.9 + 2.8 and 54.5 + 6.3%, compared to 96.1 + 2.6% in controls (P < 0.01). Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients. Myofilament Ca(2+) sensitivity was not altered, while ROS levels were significantly increased after exposure to the drug. MicroRNA expression patterns were not altered by sunitinib.CONCLUSIONS:
Sunitinib elicits a dose-dependent negative inotropic effect in myocardium, accompanied by a decline in intracellular Ca(2+) and increased ROS generation. In clinical practice, these cardiotoxic effects should be considered in cases where cardiac concentrations of sunitinib could be increased.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirróis
/
Miócitos Cardíacos
/
Inibidores de Proteínas Quinases
/
Indóis
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Contração Miocárdica
/
Antineoplásicos
Tipo de estudo:
Etiology_studies
Limite:
Aged
/
Animals
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Female
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Humans
/
Male
Idioma:
En
Revista:
BJU Int
Assunto da revista:
UROLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Áustria