Involvement of NF-kappaB and glutathione in cytotoxic effects of nitric oxide and taxol on human leukemia cells.
Nitric oxide (NO) has been shown to be cytotoxic for normal and transformed cell lines. One of the intracellular targets for NO action is glutathione (GSH). GSH determinates cellular redox potential and modulates several biological events. During oxidative and nitrosative stress, glutathione system imbalance is associated with the upregulation of gamma-glutamylcysteine synthetase (gamma-GCS) expression, which is mediated by nuclear factor kappaB (NF-kappaB). Our previous studies demonstrated a cytotoxic effect of NO and taxol on human lymphoblastic leukemia cells triggered by inhibition of NF-kappaB activity. In this study, we have demonstrated the involvement of GSH in taxol- and NO-induced cytotoxic effects on human CEM leukemia cells. NO- and taxol-induced a depletion of GSH levels in CEM cells, which was potentialized by l-buthionine-S,R-sulfoximine (BSO), an inhibitor of gamma-GCS. BSO induced an increase in nuclear translocation of NF-kappaB. However, when cells were treated with NO or taxol in association with BSO, these compounds inhibited the constitutive activity of NF-kappaB. These results suggest that oxidative and nitrosative damage in lymphoblastic leukemia cells shall be mediated by NO- and taxol-induced GSH depletion as a consequence of preventing GSH synthesis.
Santos-Silva
Maria Cláudia
MC
Department of Clinical Analysis, Center of Health Sciences, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC 88049-900, Brazil. maclau@ccs.ufsc.br
Freitas
Marta Sampaio de
MS
Assreuy
Jamil
J
D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology
D016328:NF-kappa B; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D009569:Nitric Oxide; D019328:Buthionine Sulfoximine; D026423:S-Nitroso-N-Acetylpenicillamine; D011392:Proline; D005978:Glutathione; D017239:Paclitaxel; D002330:Carmustine