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Herceptin, a recombinant humanized anti-ERBB2 monoclonal antibody, induces cardiomyocyte death.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2011 Jul 29; Vol. 411 (2), pp. 421-6. Date of Electronic Publication: 2011 Jul 02. - Publication Year :
- 2011
-
Abstract
- P53 protein levels are elevated by trastuzumab and the biologically similar rat ERBB2/HER2/NEU antibody; and that this coincides with enhanced apoptosis, increased cleaved caspase-3 levels and diminished cardiac function. We also demonstrate that MDM2 may be a regulatory target of anti-ERBB2 thereby implicating the MDM2/p53 axis as a potential molecular component for the undesirable cardiac outcomes noted with trastuzumab. Finally, we show that these MDM2/p53-mediated events are independent of both the ERK1/2 and Akt systems. In conclusion, our findings suggest that the adverse cardiac events observed with trastuzumab may stem from its negative regulation of MDM2 events which impairs p53 degradation resultantly promoting apoptosis leading to cardiac dysfunction. These observations may have important therapeutic implications since they suggest that anticancer agents that inhibit MDM2 and its downstream actions may curb tumor progression at the expense of increasing cardiac stress.<br /> (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antibodies, Monoclonal, Humanized
Heart drug effects
Heart physiopathology
Male
Mice
Mice, Inbred C57BL
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Proto-Oncogene Proteins c-mdm2 metabolism
Trastuzumab
Tumor Suppressor Protein p53 biosynthesis
Antibodies, Monoclonal adverse effects
Antineoplastic Agents adverse effects
Apoptosis drug effects
Myocytes, Cardiac drug effects
Receptor, ErbB-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 411
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 21749857
- Full Text :
- https://doi.org/10.1016/j.bbrc.2011.06.169