Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2
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De-Shen Wang1,2,*, Atish Patel2,*, Suneet Shukla3, Yun-Kai Zhang2, Yi-Jun Wang2, Rishil J. Kathawala2, Robert W. Robey4, Li Zhang1, Dong-Hua Yang5, Tanaji T. Talele2, Susan E. Bates4, Suresh V. Ambudkar3 , Rui-Hua Xu1* and Zhe-Sheng Chen2
1. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China
2. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, New York, USA
3. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
4. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
5. Biosample Repository Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
* These authors contributed equally to this work
Zhe-Sheng Chen, email:
Rui-Hua Xu, email:
Keywords: Icotinib; ABCG2; Reversal of drug resistance; thymidylate synthase; Lung cancer
Received: April 11, 2014 Accepted: June 12, 2014 Published: June 13, 2014
ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.
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