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The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy.
- Source :
-
Cancer research [Cancer Res] 2007 Nov 01; Vol. 67 (21), pp. 10428-35. - Publication Year :
- 2007
-
Abstract
- Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.
- Subjects :
- Animals
Apoptosis drug effects
Bosentan
Cardiomyopathies prevention & control
Endothelin-1 biosynthesis
ErbB Receptors metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
GATA4 Transcription Factor analysis
Lipid Peroxidation
MAP Kinase Kinase 1 metabolism
MAP Kinase Kinase 2 metabolism
Mice
Mice, Inbred C57BL
Rats
Tumor Necrosis Factor-alpha analysis
Ventricular Function, Left drug effects
Antibiotics, Antineoplastic toxicity
Cardiomyopathies chemically induced
Doxorubicin toxicity
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 67
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 17974986
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-07-1344