Open AccessWHI ‐P154 enhances the chemotherapeutic effect of anticancer agents in ABCG 2‐overexpressing cells
Author(s) -
Zhang Hui,
Zhang YunKai,
Wang YiJun,
Kathawala Rishil J.,
Patel Atish,
Zhu Hua,
Sodani Kamlesh,
Talele Tanaji T.,
Ambudkar Suresh V.,
Chen ZheSheng,
Fu LiWu
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12462
Subject(s) - abcg2 , abcc1 , multidrug resistance associated protein 2 , atp binding cassette transporter , efflux , pharmacology , tyrosine kinase inhibitor , chemistry , multiple drug resistance , p glycoprotein , tyrosine kinase , intracellular , transporter , drug resistance , microbiology and biotechnology , biology , biochemistry , receptor , genetics , cancer , gene , antibiotics
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.