Lapatinib Antagonizes Multidrug Resistance-Associated Protein 1-Mediated Multidrug Resistance by Inhibiting Its Transport Function
Lapatinib, a tyrosine kinase inhibitor, is used in the treatment of advanced or metastatic breast cancer overexpressing human epidermal receptor 2 (HER2). Lapatinib can modulate the function of ATP-binding cassette (ABC) transporters (ABCB1 and ABCG2), which are the major mechanism responsible for multidrug resistance (MDR) in cancer. In this study, we investigated the effect of lapatinib on multidrug resistance-associated protein 1 (MRP1 (ABCC1)), MRP2 (ABCC2), MRP4 (ABCC4) and lung relative resistance protein (LRP) drug efflux pumps. We demonstrated that lapatinib could enhance the efficacy of conventional chemotherapeutic agents in MRP1-overexpressing cells in vitro and in vivo, but no effect in MRP2-, MPR4- and LRP-overexpressing cells. Furthermore, lapatinib significantly increased the accumulation of rhodamine 123 (Rho123) and doxorubicin (DOX) in MRP1-overexpressing cells. However, lapatinib did not alter the protein or mRNA expression levels of MRP1. Further studies showed that the level of phosphorylation of AKT and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were not altered at the indicated concentrations of lapatinib. In conclusion, lapatinib enhanced the efficacy of conventional chemotherapeutic agents in MRP1-overexpressing cells by inhibiting MRP1 transport function without altering the level of AKT or ERK1/2 phosphorylation. These findings will encourage the clinical research of lapatinib combined with conventional chemotherapeutic drugs in MRP1-overexpressing cancer patients.
We thank Zhe-Sheng Chen (St. John’s University, Queens, NY, USA) for the NIH3T3 and NIH3T3/MRP4-2 cell lines and professor Kenneth To (The Chinese University of Hong Kong) for comments. The work was supported by grants from National Science and Technology Major Projects of the National Basic Research Program (973 Program) of China (2012CB967004 for L-w Fu), 863 Program of China (2012AA02A303 for L-w Fu), National Natural Sciences Foundation of China (81061160507 and 81072669 for L-w Fu), Nature Science Foundation (excellent PhD dissertation foundation) of the Guangdong province (8400-3226201) and Natural Science Foundation of Guangzhou (12C32061587).
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