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Abstract
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.
Highlights
Chemotherapy is the only systemic treatment for many malignant tumors
We explored the effect of lapatinib on the efficacy of conventional chemotherapeutic agents in MRP1, MRP2, MRP4- and lung relative resistance protein (LRP)-overexpressing cancer cells in vitro and in vivo
Monoclonal antibodies against MRP1, MRP2, MRP4, LRP, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), p-ERK, AKT and p-AKT were from Santa Cruz Biotechnology (Santa Cruz, CA, USA)
Summary
Chemotherapy is the only systemic treatment for many malignant tumors. the occurrence of multidrug resistance (MDR) limits the application of chemotherapy. The major mechanism responsible for MDR is the overexpression of ATP-binding cassette (ABC) transporters [1]. ABC transporters decrease drug intracellular accumulation in cancer cells by pumping lots of anticancer drugs out of the cells with energy derived from ATP hydrolysis, resulting in chemotherapy resistance [2]. The major members of ABC transporters leading to MDR include ABCB1 (P-glycoprotein [P-gp]), ABCC1 (multidrug resistance–associated protein 1 [MRP1]) and ABCG2 (breast cancer resistant protein [BCRP]) [3,4]. These proteins owned the ability of conferring resistance to chemotherapeutic agents
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