title: Human ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1.
abstract: The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) is associated with poor prognosis in many types of cancer. Consequently, Plk1 has emerged as a valid therapeutic target for anticancer drug design. Volasertib is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting cell cycle arrest at nanomolar concentrations. However, the risk of developing drug resistance, which is often associated with the overexpression of the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein), can present a therapeutic challenge for volasertib and many other therapeutic drugs. Although volasertib is highly effective against the proliferation of numerous cancer cell lines, we found that the overexpression of ABCB1 in cancer cells leads to cellular resistance to volasertib and reduces the level of volasertib-stimulated G2/M cell cycle arrest and subsequent onset of apoptosis. Furthermore, we demonstrate that volasertib competitively inhibits the function of ABCB1 and stimulates the basal ATPase activity of ABCB1 in a concentration-dependent manner, which is consistent with substrate transport by ABCB1. More importantly, we discovered that the coadministration of an inhibitor or drug substrate of ABCB1 restored the anticancer activity of volasertib in ABCB1-overexpressing cancer cells. In conclusion, the results of our study reveal that ABCB1 negatively affects the efficacy of volasertib and supports its combination with a modulator of ABCB1 to improve clinical responses.
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.forename: Sung-Han
authors.initials: SH
authors.lastname: Hsiao
authors.forename: Shi-Yu
authors.initials: SY
authors.lastname: Luo
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.affiliation: Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital , Tao-Yuan, Taiwan.
authors.forename: Chiun-Wei
authors.initials: CW
authors.lastname: Huang
authors.forename: Sheng-Chieh
authors.initials: SC
authors.lastname: Hsu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C513055:ABCB1 protein, human; C541363:BI 6727
keywords: ABCB1; Polo-like kinase 1; multidrug resistance; volasertib