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

Autor: Li Ming Chen, Robert W. Robey, Charles R. Ashby, Zhe-Sheng Chen, Li Wu Fu, Si Rong Wang, Amit K. Tiwari, Yong Ju Liang, Xiao Dong Su, Chun Ling Dai, Cheng Jun Shi, Yan Huang, Chung-Pu Wu, Dong Geng Liu, Suresh V. Ambudkar
Rok vydání: 2008
Předmět:
Cancer Research
ATP Binding Cassette Transporter
Subfamily B
Paclitaxel
Abcg2
medicine.drug_class
Mice
Nude
ATP-binding cassette transporter
Biology
Pharmacology
Transfection
Lapatinib
Article
Tyrosine-kinase inhibitor
Mice
Neoplasms
Antineoplastic Combined Chemotherapy Protocols
medicine
ATP Binding Cassette Transporter
Subfamily G
Member 2
Animals
Humans
ATP Binding Cassette Transporter
Subfamily B
Member 1
ABCC10
skin and connective tissue diseases
Cells
Cultured
P-glycoprotein
Adenosine Triphosphatases
Dose-Response Relationship
Drug
Xenograft Model Antitumor Assays
Drug Resistance
Multiple
Neoplasm Proteins
Tumor Burden
Up-Regulation
Gene Expression Regulation
Neoplastic
Oncology
Drug Resistance
Neoplasm
Cancer cell
Quinazolines
biology.protein
ATP-Binding Cassette Transporters
sense organs
Tyrosine kinase
medicine.drug
Zdroj: Cancer Research. 68:7905-7914
ISSN: 1538-7445
0008-5472
Popis: 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 E217βG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [125I]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. [Cancer Res 2008;68(19):7905–14]
Databáze: OpenAIRE
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