title: Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro.
abstract: Dinaciclib is a novel cyclin-dependent kinase inhibitor (CDKI) with significant activity against various cancers in vitro and in vivo. ABC efflux transporters play an important role in drug disposition and are responsible for multidrug resistance in cancer cells. Inhibitors and substrates of these transporters may participate in pharmacokinetic drug-drug interactions (DDIs) that alter drug disposition during pharmacotherapy. To assess such risks associated with dinaciclib we evaluated its possible effects on efflux activities of ABCB1, ABCC1 and ABCG2 transporters in vitro. Monolayer transport, XTT cell proliferation, ATPase and intracellular accumulation assays were employed. Here, we show that the transport ratio of dinaciclib was far higher across monolayers of MDCKII-ABCB1 and MDCKII-ABCG2 cells than across MDCKII parental cell layers, demonstrating that dinaciclib is a substrate of ABCB1 and ABCG2. In addition, overexpression of ABCB1, ABCG2 and ABCC1 conferred resistance to dinaciclib in MDCKII cells. In ATPase assays, dinaciclib decreased stimulated ATPase activity of ABCB1, ABCG2 and ABCC1, confirming it has interactive potential toward all three transporters. Moreover, dinaciclib significantly inhibited ABCC1-mediated efflux of daunorubicin (EC50=18 μM). The inhibition of ABCC1 further led to a synergistic effect of dinaciclib in both MDCKII-ABCC1 and human cancer T47D cells, when applied in combination with anticancer drugs. Taken together, our results suggest that ABC transporters can substantially affect dinaciclib transport across cellular membranes, leading to DDIs. The DDIs of dinaciclib with ABCC1 substrate chemotherapeutics might be exploited in novel cancer therapies.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: cihad6aa@faf.cuni.cz.
authors: Daniela
authors: D
authors: Cihalova
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: martina.ceckova@faf.cuni.cz.
authors: Martina
authors: M
authors: Ceckova
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: radim.kucera@faf.cuni.cz.
authors: Radim
authors: R
authors: Kucera
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: jiri.klimes@faf.cuni.cz.
authors: Jiri
authors: J
authors: Klimes
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: frantisek.staud@faf.cuni.cz.
authors: Frantisek
authors: F
authors: Staud
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology*; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007212:Indolizines; D061985:Madin Darby Canine Kidney Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases; D007212:Indolizines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C553669:dinaciclib; C421109:multidrug resistance-associated protein 1
keywords: ABCB1; ABCC1; ABCG2; Cytotoxicity; Dinaciclib; Dinaciclib (PubChem CID: 46926350); Multidrug resistance