title: WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.
abstract: 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 ABCG2-overexpressing cells to its substrates. WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance. Moreover, WHI-P154 produced a significant increase in the intracellular accumulation of [³H]-mitoxantrone in ABCG2-overexpressing cells. The expression levels nor the localization of the ABCG2 protein was altered after treatment of ABCG2-overexpressing cells with WHI-P154. Further studies indicated that WHI-P154 enhanced the ATPase activity of ABCG2 at low concentrations (<10 μM). Additionally, a docking model predicted the binding conformation of WHI-P154 within the transmembrane region of homology-modeled human ABCG2 transporter. Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Yun-Kai
authors.initials: YK
authors.lastname: Zhang
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Wang
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.forename: Atish
authors.initials: A
authors.lastname: Patel
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Sodani
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; D011799:Quinazolines; C113888:WHI P154
keywords: ABCG2 protein; ATP-binding cassette transporters; WHI-P154; multidrug resistance; tyrosine kinase