TY - JOUR T1 - 9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH JF - Anticancer Research JO - Anticancer Res SP - 3163 LP - 3168 VL - 33 IS - 8 AU - PAVLA PLAČKOVÁ AU - NELA ROZUMOVÁ AU - HUBERT HŘEBABECKÝ AU - MICHAL ŠÁLA AU - RADIM NENCKA AU - TOMÁŠ ELBERT AU - ALEXANDRA DVOŘÁKOVÁ AU - IVAN VOTRUBA AU - HELENA MERTLÍKOVÁ-KAISEROVÁ Y1 - 2013/08/01 UR - http://ar.iiarjournals.org/content/33/8/3163.abstract N2 - 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. ER -