title: ATP-binding cassette B1 transports seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor.
abstract: Seliciclib, a cyclin-dependent kinase inhibitor, is a promising candidate to treat a variety of cancers. Pharmacokinetic studies have shown high oral bioavailability but limited brain exposure to the drug. This study shows that seliciclib is a high-affinity substrate of ATP-binding cassette B1 (ABCB1) because it activates the ATPase activity of the transporter with an EC(50) of 4.2 μM and shows vectorial transport in MDCKII-MDR1 cells, yielding an efflux ratio of 8. This interaction may be behind the drug's limited penetration of the blood-brain barrier. ABCB1 overexpression, on the other hand, does not confer resistance to the drug in the models tested. These findings should be considered when treatment strategies using seliciclib are designed.
authors.affiliation: Solvo Biotechnology, Szeged, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Rajnai
authors.forename: Dóra
authors.initials: D
authors.lastname: Méhn
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Beéry
authors.forename: Alper
authors.initials: A
authors.lastname: Okyar
authors.forename: Márton
authors.initials: M
authors.lastname: Jani
authors.forename: Gábor K
authors.initials: GK
authors.lastname: Tóth
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
authors.forename: Peter
authors.initials: P
authors.lastname: Krajcsi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001692:Biological Transport; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D011687:Purines / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077546:Roscovitine; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases; D000251:Adenosine Triphosphatases