title: Herceptin, a recombinant humanized anti-ERBB2 monoclonal antibody, induces cardiomyocyte death.
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.
authors.affiliation: Division of Cardiac Surgery, The Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. singhkk@smh.ca
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.forename: Praphulla C
authors.initials: PC
authors.lastname: Shukla
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Jesse I
authors.initials: JI
authors.lastname: Wolfstadt
authors.forename: Milan
authors.initials: M
authors.lastname: Gupta
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051736:Proto-Oncogene Proteins c-mdm2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse