Title of article :
AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance
Author/Authors :
Zhang، نويسنده , , Hui and Wang، نويسنده , , Yijun and Zhang، نويسنده , , Yun-Kai and Wang، نويسنده , , De-Shen and Kathawala، نويسنده , , Rishil J. and Patel، نويسنده , , Atish and Talele، نويسنده , , Tanaji T. and Chen، نويسنده , , Zhe-Sheng and Fu، نويسنده , , Li-Wu، نويسنده ,
Abstract :
AST1306, an inhibitor of EGFR and ErbB2, is currently in phase I of clinical trials. We evaluated the effect of AST306 on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters. We found that AST1306 significantly sensitized the ABC subfamily G member 2 (ABCG2)-overexpressing cells to ABCG2 substrate chemotherapeutics. AST1306 significantly increased intracellular accumulation of [3H]-mitoxantrone in ABCG2-overexpressing cells by blocking ABCG2 efflux function. Moreover, AST1306 stimulated the ATPase activity of ABCG2. Homology modeling predicted the binding conformation of AST1306 to be within the transmembrane region of ABCG2. In conclusion, AST1306 could notably reverse ABCG2-mediated MDR.
Keywords :
AST1306 , ATP-binding cassette transporters , ABCG2 , Multidrug resistance
