title: Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 transporters and their potential to overcome multidrug resistance in vitro.
abstract: OBJECTIVE
  ATP-binding cassette (ABC) transporters play an important role in multidrug resistance (MDR) toward anticancer drugs. Here, we evaluated interactions of cyclin-dependent kinase inhibitors (CDKi) AT-7519, flavopiridol and SNS-032 with the following ABC transporters in vitro: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated protein 1 (ABCC1).
  
  
  METHODS
  Inhibitory potency of studied CDKi to the transporters was evaluated by accumulation assays using fluorescent substrates and MDCKII cells overexpressing human ABCB1, ABCG2 or ABCC1. Resistance of transporter-expressing cells to the CDKi was evaluated by XTT proliferation assay. Observed interactions of CDKi were verified by ATPase assay in ABC transporter-expressing Sf9 membrane vesicles. Combination index analysis was additionally performed in ABC transporter-expressing cancer cell lines, HepG2 and T47D.
  
  
  RESULTS
  Flavopiridol showed a significant inhibitory potency toward ABCG2 and ABCC1. SNS-032 also decreased ABCG2-mediated efflux, while AT-7519 failed to inhibit ABCB1, ABCG2 or ABCC1. Both flavopiridol and SNS-032 showed synergistic antiproliferative effects in combination with relevant ABC transporter substrates such as daunorubicin and topotecan in cancer cells. ABCB1 was found to confer significant resistance to AT-7519 and SNS-032, but not to flavopiridol. In contrast, ABCG2 and ABCC1 conferred resistance to flavopiridol, but not to AT-7519 and SNS-032.
  
  
  CONCLUSIONS
  Our data provide detailed information on interactions of flavopiridol, SNS-032 and AT-7519 with ABC transporters, which may help elucidate the pharmacokinetic behavior and toxicity of these compounds. Moreover, we show the ability of flavopiridol and SNS-032, but not AT-7519, to overcome ABC transporter-mediated MDR.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic, cihad6aa@faf.cuni.cz.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cihalova
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D010080:Oxazoles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C531230:4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; D018528:ATP-Binding Cassette Transporters; D005419:Flavonoids; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; C077990:alvocidib