title: Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of Polo-like kinase 1.
abstract: The overexpression of the serine/threonine specific Polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. BI 2536 is the first selective inhibitor of Plk1 that inhibits cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to BI 2536 is prone to present a significant therapeutic challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1, ABCC1 and ABCG2. Here, we discovered that overexpressing of either ABCB1 or ABCG2 is a novel mechanism of acquired resistance to BI 2536 in human cancer cells. Moreover, BI 2536 stimulates the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner, and inhibits the drug substrate transport mediated by these transporters. More significantly, the reduced chemosensitivity and BI 2536-mediated G2/M cell cycle arrest in cancer cells overexpressing either ABCB1 or ABCG2 can be significantly restored in the presence of selective inhibitor or other chemotherapeutic agents that also interact with ABCB1 and ABCG2, such as tyrosine kinase inhibitors nilotinib and lapatinib. Taken together, our findings indicate that in order to circumvent ABCB1 or ABCG2-mediated acquired resistance to BI 2536, a combined regimen of BI 2536 and inhibitors or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic.
authors: Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan. Electronic address: wuchung@mail.cgu.edu.tw.
authors: Chung-Pu
authors: CP
authors: Wu
authors: Sung-Han
authors: SH
authors: Hsiao
authors: Hong-May
authors: HM
authors: Sim
authors: Shi-Yu
authors: SY
authors: Luo
authors: Wei-Cherng
authors: WC
authors: Tuo
authors: Hsing-Wen
authors: HW
authors: Cheng
authors: Yan-Qing
authors: YQ
authors: Li
authors: Yang-Hui
authors: YH
authors: Huang
authors: Suresh V
authors: SV
authors: Ambudkar
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D000077341:Lapatinib; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D011743:Pyrimidines; D011799:Quinazolines; D000097869:Polo-Like Kinase 1; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C518477:BI 2536; C498826:nilotinib
keywords: 3-(4,5-dimethylthiazol-yl)-2,5-diphenyllapatinibrazolium bromide; ABC; ABC transporter; ATP-binding cassette; BI 2536; FTC; Fumitremorgin C; MDR; MTT; Multidrug resistance; PhA; Plk-1; Polo-like kinase 1; Vi; multidrug resistance; pheophorbide A; sodium orthovanadate
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