Felbamate-induced apoptosis of hematopoietic cells is mediated by redox-sensitive and redox-independent pathways.
Felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an approved antiepileptic drug shown to be effective in a variety of seizure disorders refractory to other treatments. However, its use has been restricted because of association with occurrence of rare cases of aplastic anemia and hepatic failure. Since it was shown that FBM metabolism requires glutathione (GSH), we used two experimental protocols to determine if the effects of specific metabolites were sensitive to redox pathways. FBM and its metabolite W873 (2-phenyl-1,3-propanediol monocarbamate), at 0.1 mg/ml, induced increased apoptosis of bone marrow cells from B10.AKM mice as compared with B10.BR mice. Study of the effects of the drug on human promonocytic cell line U937 cells showed that FBM and the metabolite W2986 [2-(4-hydroxyphenyl)-1,3 propanediol dicarbamate], at higher concentrations (0.5 mg/ml), induced apoptosis in this cell line. We also observed that while FBM and its metabolites induced increased apoptosis of B cells with reduced intracellular GSH levels, addition of exogenous GSH decreased apoptosis induced by W873 but did not significantly affect apoptosis induced by FBM or W2986. Our results suggest that, at concentrations used during the present investigations, FBM metabolites induce apoptosis via redox-sensitive and redox-independent pathways.
Husain
Zaheed
Z
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. zaheed_husain@dfci.harvard.edu
Pinto
Clara
C
Sofia
R Duane
RD
Yunis
Edmond J
EJ
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D000078328:Felbamate; D005978:Glutathione / Q000172:deficiency; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020298:U937 Cells
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D005978:Glutathione; D000078328:Felbamate