ATP-binding cassette B1 transports seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor.
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.
Rajnai
Zsuzsanna
Z
Solvo Biotechnology, Szeged, Hungary.
Méhn
Dóra
D
Beéry
Erzsébet
E
Okyar
Alper
A
Jani
Márton
M
Tóth
Gábor K
GK
Fülöp
Ferenc
F
Lévi
Francis
F
Krajcsi
Peter
P
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
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