title: Lapatinib antagonizes multidrug resistance-associated protein 1-mediated multidrug resistance by inhibiting its transport function.
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.
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Shao-lin
authors.initials: SL
authors.lastname: Ma
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Ya-peng
authors.initials: YP
authors.lastname: Hu
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhen-cong
authors.initials: ZC
authors.lastname: Huang
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yi-fan
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiao-kun
authors.initials: XK
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Li-wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D000077341:Lapatinib; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D014750:Vincristine; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1
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