The authors declare that they have no competing interests.
ARRY-334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP-Binding Cassette Subfamily G Member 2
Article first published online: 17 JUN 2014
© 2014 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 115, Issue 8, pages 1381–1391, August 2014
How to Cite
Wang, D.-S., Patel, A., Sim, H.-M., Zhang, Y.-K., Wang, Y.-J., Kathawala, R. J., Zhang, H., Talele, T. T., Ambudkar, S. V., Xu, R.-H. and Chen, Z.-S. (2014), ARRY-334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP-Binding Cassette Subfamily G Member 2. J. Cell. Biochem., 115: 1381–1391. doi: 10.1002/jcb.24787
- Issue published online: 17 JUN 2014
- Article first published online: 17 JUN 2014
- Accepted manuscript online: 17 FEB 2014 07:10AM EST
- Manuscript Accepted: 12 FEB 2014
- Manuscript Received: 26 DEC 2013
- National Institutes of Health. Grant Number: 1R15CA143701
- St. John’s University Research Seed Grant. Grant Number: 579–1110-7002
- Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research
- Scholarship Award for Excellent Doctoral Student granted by Ministry of Education. Grant Number: 84000–3191003
- International Program of 985 Project, Sun Yat-sen University for overseas study at St. John’s University
- MULTIDRUG RESISTANCE;
- TYROSINE KINASE INHIBITOR;
- LUNG CANCER
ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. Our results demonstrated that ARRY-334543 (1.0 μM) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [125I]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 μM) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity toward ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentrations did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2. We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2. J. Cell. Biochem. 115: 1381–1391, 2014. © 2014 Wiley Periodicals, Inc.