Olomoucine II and purvalanol A inhibit ABCG2 transporter in vitro and in situ and synergistically potentiate cytostatic effect of mitoxantrone
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
22173067
DOI
10.1016/j.phrs.2011.11.017
PII: S1043-6618(11)00297-0
Knihovny.cz E-zdroje
- MeSH
- ABC transportér z rodiny G, člen 2 MeSH
- ABC transportéry antagonisté a inhibitory metabolismus MeSH
- benzimidazoly metabolismus MeSH
- buněčné linie MeSH
- chemorezistence účinky léků MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory MeSH
- cytostatické látky farmakologie MeSH
- glibenklamid metabolismus MeSH
- lidé MeSH
- mitoxantron farmakologie MeSH
- nádorové proteiny antagonisté a inhibitory metabolismus MeSH
- nádory prsu farmakoterapie MeSH
- protinádorové látky farmakologie MeSH
- puriny farmakologie MeSH
- synergismus léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine MeSH Prohlížeč
- ABC transportér z rodiny G, člen 2 MeSH
- ABC transportéry MeSH
- ABCG2 protein, human MeSH Prohlížeč
- benzimidazoly MeSH
- bisbenzimide ethoxide trihydrochloride MeSH Prohlížeč
- cyklin-dependentní kinasy MeSH
- cytostatické látky MeSH
- glibenklamid MeSH
- mitoxantron MeSH
- nádorové proteiny MeSH
- olomoucine II MeSH Prohlížeč
- protinádorové látky MeSH
- puriny MeSH
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.
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