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ATP-Binding Cassette B1 Transports Seliciclib ( R -Roscovitine), a Cyclin-Dependent Kinase Inhibitor

2010; American Society for Pharmacology and Experimental Therapeutics; Volume: 38; Issue: 11 Linguagem: Inglês

10.1124/dmd.110.032805

1521-009X

Zsuzsanna Rajnai, Dóra Méhn, Erzsébet Beéry, Alper Okyar, Márton Jani, Gábor Tóth, Ferenc Fülöp, Francis Lévi, Péter Krajcsi,

Cancer therapeutics and mechanisms

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 drug9s 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.