9-Norbornyl-6-chloropurine is a novel antileukemic compound interacting with cellular GSH
Jazyk angličtina Země Řecko Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
23898074
PII: 33/8/3163
Knihovny.cz E-zdroje
- Klíčová slova
- Substituted 6-chloropurines, carbocyclic nucleoside analogs, glutathione depletion, glutathione-S-transferase,
- MeSH
- biologický transport účinky léků MeSH
- Caco-2 buňky MeSH
- epitelové buňky účinky léků metabolismus MeSH
- glutathion metabolismus MeSH
- glutathiontransferasa antagonisté a inhibitory metabolismus MeSH
- inhibitory cytochromu P450 MeSH
- leukemie farmakoterapie patologie MeSH
- lidé MeSH
- protinádorové látky chemie farmakologie terapeutické užití MeSH
- puriny chemie farmakologie terapeutické užití MeSH
- screeningové testy protinádorových léčiv MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- xanthinoxidasa antagonisté a inhibitory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 6-chloropurine MeSH Prohlížeč
- 9-norbornyl-6-chloropurine MeSH Prohlížeč
- glutathion MeSH
- glutathiontransferasa MeSH
- inhibitory cytochromu P450 MeSH
- protinádorové látky MeSH
- puriny MeSH
- systém (enzymů) cytochromů P-450 MeSH
- xanthinoxidasa MeSH
AIM: 6-Chloropurines substituted at position 9 with bicyclic skeletons represent promising chemotherapeutic agents. We explored the metabolism and membrane transport of 9-norbornyl-6-chloropurine (NCP) aiming to understand its mechanism of action. MATERIALS AND METHODS: The metabolism of NCP was studied in vitro in whole cells (CCRF-CEM), cellular extracts, subcellular fractions and purified enzymes. Transport experiments were conducted in Caco-2 cell monolayers. RESULTS: Three metabolites were identified, a glutathione conjugate (NCP-GS), NCP-cysteinylglycine and NCP-cysteine. Both glutathione-S-transferase inhibition and glutathione (GSH) depletion prevented metabolite formation and increased the cytotoxicity of NCP. Transepithelial transport (Caco-2) indicated good permeability, with Papp (12.6±0.3) ×10(-5) cm/s. Importantly, the drug induced glutathione depletion in treated cells and affected the activity of several GSH-dependent enzymes. CONCLUSION: The novel nucleoside analog NCP represents a promising orally available antileukemic agent, acting through lowering of GSH levels in tumor cells.
