@article {PLA{\v C}KOV{\'A}3163, author = {PAVLA PLA{\v C}KOV{\'A} and NELA ROZUMOV{\'A} and HUBERT H{\v R}EBABECK{\'Y} and MICHAL {\v S}{\'A}LA and RADIM NENCKA and TOM{\'A}{\v S} ELBERT and ALEXANDRA DVO{\v R}{\'A}KOV{\'A} and IVAN VOTRUBA and HELENA MERTL{\'I}KOV{\'A}-KAISEROV{\'A}}, title = {9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH}, volume = {33}, number = {8}, pages = {3163--3168}, year = {2013}, publisher = {International Institute of Anticancer Research}, abstract = {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{\textpm}0.3) {\texttimes}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.}, issn = {0250-7005}, URL = {https://ar.iiarjournals.org/content/33/8/3163}, eprint = {https://ar.iiarjournals.org/content/33/8/3163.full.pdf}, journal = {Anticancer Research} }