title: Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1.
abstract: Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis, and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concentrations. However, as is the case for many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we observed a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concentration-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that, by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis, and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.
authors.affiliation: Department of Physiology and Pharmacology, ‡Graduate Institute of Biomedical Sciences, and §Molecular Medicine Research Center, College of Medicine, Chang Gung University , Tao-Yuan 333, Taiwan.
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.forename: Sung-Han
authors.initials: SH
authors.lastname: Hsiao
authors.forename: Shi-Yu
authors.initials: SY
authors.lastname: Luo
authors.forename: Wei-Cherng
authors.initials: WC
authors.lastname: Tuo
authors.forename: Ching-Ya
authors.initials: CY
authors.lastname: Su
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Li
authors.forename: Yang-Hui
authors.initials: YH
authors.lastname: Huang
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D000097869:Polo-Like Kinase 1; C513055:ABCB1 protein, human; C561573:GSK 461364
keywords: ABCB1; GSK461364; Polo-like kinase 1; multidrug resistance