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The Dual-Targeted HER1/HER2 Tyrosine Kinase Inhibitor Lapatinib Strongly Potentiates the Cardiac Myocyte-Damaging Effects of Doxorubicin.
MedLine Citation:
PMID:  22948710     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The anticancer drug lapatinib (Tykerb) is a dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways that have been shown in clinical trials to display some cardiotoxicity. Because trastuzumab also targets HER2 receptors, the lapatinib/doxorubicin combination provides a good model to probe the mechanism of the increased cardiotoxicity caused by the concurrent use of trastuzumab and doxorubicin. Using a neonatal rat cardiac myocyte model, we have investigated the ability of lapatinib alone and in combination with doxorubicin to damage myocytes. Lapatinib treatment alone only slightly induced myocyte damage. However, doxorubicin-induced myocyte damage was greatly potentiated by the addition of nanomolar lapatinib concentrations. Lapatinib alone treatment decreased phosphorylated ERK (MAPK), which may have, in part, contributed to the increased myocyte damage. As measured by flow cytometry, lapatinib-treated myocytes displayed an increased accumulation of doxorubicin. As lapatinib is a strong inhibitor of several ATP-dependent ABC-type efflux transporters, this likely occurred because lapatinib blocked doxorubicin efflux, thereby increasing intracellular doxorubicin concentrations and, thus, increasing myocyte damage. These results suggest that the clinical use of concurrent doxorubicin and lapatinib should be approached with care due to the possibility of lapatinib increasing doxorubicin cardiotoxicity.
Authors:
Brian B Hasinoff; Daywin Patel; Xing Wu
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-5
Journal Detail:
Title:  Cardiovascular toxicology     Volume:  -     ISSN:  1559-0259     ISO Abbreviation:  Cardiovasc. Toxicol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101135818     Medline TA:  Cardiovasc Toxicol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada, B_Hasinoff@UManitoba.ca.
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