title: Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.
abstract: Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.
authors.affiliation: State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Chun-ling
authors.initials: CL
authors.lastname: Dai
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Su
authors.forename: Si-Rong
authors.initials: SR
authors.lastname: Wang
authors.forename: Dong-geng
authors.initials: DG
authors.lastname: Liu
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Yong-ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Li-ming
authors.initials: LM
authors.lastname: Chen
authors.forename: Cheng-Jun
authors.initials: CJ
authors.lastname: Shi
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Li-wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D011799:Quinazolines; D000077341:Lapatinib; D000251:Adenosine Triphosphatases; D017239:Paclitaxel