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ATP ‐binding cassette ( ABC ) transmembrane proteins evidently decrease the intracellular accumulation of substrate chemotherapeutic drugs by extruding them against a concentration gradient, thereby inducing drug resistance. Here we reported the effect of  WHI ‐P154, an irreversible inhibitor of Janus kinase 3 and epidermal growth factor receptor tyrosine kinases, on reversing  ABC  transporters‐mediated drug resistance. We found that  WHI ‐P154 significantly enhanced the sensitivity of  ABCG 2‐overexpressing cells to its substrates.  WHI ‐P154 moderately sensitized  ABCB 1‐overexpressing  KB ‐C2 cells to its substrates whereas showed no sensitizing effect on  ABCC 1‐,  ABCC 2 or  ABCC 10‐mediated drug resistance. Moreover,  WHI ‐P154 produced a significant increase in the intracellular accumulation of [³H]‐mitoxantrone in  ABCG 2‐overexpressing cells. The expression levels nor the localization of the  ABCG 2 protein was altered after treatment of  ABCG 2‐overexpressing cells with  WHI ‐P154. Further studies indicated that  WHI ‐P154 enhanced the  ATP ase activity of  ABCG 2 at low concentrations (<10 μM). Additionally, a docking model predicted the binding conformation of  WHI ‐P154 within the transmembrane region of homology‐modeled human  ABCG 2 transporter. Collectively, these findings highlighted  WHI ‐P154 could significantly reverse  ABCG 2‐mediated multidrug drug resistance by directly blocking the efflux function.

WHI ‐P154 enhances the chemotherapeutic effect of anticancer agents in ABCG 2‐overexpressing cells