title: Olomoucine II and purvalanol A inhibit ABCG2 transporter in vitro and in situ and synergistically potentiate cytostatic effect of mitoxantrone.
abstract: Inhibition of cyclin-dependent kinases by specific small molecules, purine cyclin-dependent kinase inhibitors (CDKi), has become a promising strategy for cancer treatment. Although pharmacodynamic properties of these compounds have been studied extensively, their pharmacokinetic behavior has not been addressed in detail. In this study, we investigated possible inhibitory effect of five purine CDKi on breast cancer resistance protein (ABCG2) transport activity employing in vitro transport and accumulation methods in MCDKII cells transduced with human ABCG2. Hoechst 33342 and glyburide were used as model ABCG2 substrates for these experiments. In addition, in situ method of dually perfused rat term placenta was utilized to confirm our in vitro results at the organ level. Fumitremorgin C was used as a model inhibitor of ABCG2 for comparison purposes. We demonstrate significant inhibition of ABCG2 by four of the five CDKi tested. Regarding their ABCG2-inhibitory potencies, the investigated compounds can be ranked as follows: purvalanol A>olomoucine II≈fumitremorgin C>roscovitine≈bohemine, with slight differences among substrates, concentrations and methods used. Based on our findings, it is reasonable to expect a substantial impact of the studied CDKi on the pharmacokinetic and pharmacodynamic behavior of concomitantly administered ABCG2 substrates. Moreover, using combination index method of Chou-Talalay, we confirmed that the strongest inhibitors, purvalanol A and olomoucine II, can synergistically potentiate cytostatic effect of mitoxantrone, an ABCG2 substrate, in ABCG2 expressing cell lines.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Hofman
authors.forename: Davoud
authors.initials: D
authors.lastname: Ahmadimoghaddam
authors.forename: Lenka
authors.initials: L
authors.lastname: Hahnova
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D054697:Cytostatic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005905:Glyburide / Q000378:metabolism; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*
chemical_list: C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D054697:Cytostatic Agents; D009363:Neoplasm Proteins; D011687:Purines; C475587:olomoucine II; D008942:Mitoxantrone; D018844:Cyclin-Dependent Kinases; C017807:bisbenzimide ethoxide trihydrochloride; D005905:Glyburide