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Objective: Linsitinib, a novel dual insulin-like growth factor 1 (IGF-1R)/insulin receptor (IR) kinase inhibitor in phase Ⅲ clinical trial, was investigated the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters.Methods: Cytotoxicity was determined by MTT assay.The expression levels of ABCG2 and ABCC10 were detected by Western blot.The intracellular accumulation and efflux of [3H]-MX and [3H]-paclitaxel were measured by Scintillation Counter.Results: We found that linsitinib significantly enhanced the efficacy of mitoxantrone (MX) and SN-38 in ABCG2 overexpressing cells; paclitaxel, docetaxel and vinblastine in ABCC10 overexpressing cells, respectively.Linsitinib moderately enhanced the cytotoxicity of vincristine in cells overexpressing ABCB1, whereas it did not alter the cytotoxicity of substrates in ABCC1 overexpressing cells.Furthermore, linsitinib significantly increased the intracellular accumulation and decreased the efflux of [3H]-MX in ABCG2 overexpressing cells and [3H]-paclitaxel in ABCC10 overexpressing cells.Linsitinib, did significantly alter the expression levels and localization of neither the ABCG2 nor ABCC10 proteins.Furthermore,linsitinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner.These suggest that linsitinib attenuates ABCG2-and ABCC10-mediated MDR by inhibiting their function.