9-Norbornyl-6-chloropurine is a novel antileukemic compound interacting with cellular GSH
Language English Country Greece Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
23898074
PII: 33/8/3163
Knihovny.cz E-resources
- Keywords
- Substituted 6-chloropurines, carbocyclic nucleoside analogs, glutathione depletion, glutathione-S-transferase,
- MeSH
- Biological Transport drug effects MeSH
- Caco-2 Cells MeSH
- Epithelial Cells drug effects metabolism MeSH
- Glutathione metabolism MeSH
- Glutathione Transferase antagonists & inhibitors metabolism MeSH
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Leukemia drug therapy pathology MeSH
- Humans MeSH
- Antineoplastic Agents chemistry pharmacology therapeutic use MeSH
- Purines chemistry pharmacology therapeutic use MeSH
- Drug Screening Assays, Antitumor MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Chromatography, High Pressure Liquid MeSH
- Xanthine Oxidase antagonists & inhibitors metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 6-chloropurine MeSH Browser
- 9-norbornyl-6-chloropurine MeSH Browser
- Glutathione MeSH
- Glutathione Transferase MeSH
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Antineoplastic Agents MeSH
- Purines MeSH
- Cytochrome P-450 Enzyme System MeSH
- Xanthine Oxidase 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.