Regulation of tumour cell sensitivity to TNF-induced oxidative stress and cytotoxicity: role of glutathione.
Glutathione (GSH) and the rate of cellular proliferation determine tumour cell sensitivity to tumour necrosis factor (TNF). Buthionine sulphoximine (BSO), a selective inhibitor of GSH synthesis, inhibits tumour growth and increases recombinant human TNF (rhTNF)-alpha cytoxicity in vitro. Administration of sublethal doses of rhTNF-alpha to Ehrlich ascites-tumour (EAT)-bearing mice induces oxidative stress (as measured by increases in intracellular peroxide levels, O2.- generation and mitochondrial GSSG). ATP-induced selective GSH depletion, when combined with rhTNF-alpha administration, affords a 61% inhibition of tumour growth and results in a significant extent of host survival. Administration of N-acetylcysteine (NAC) or GSH ester abolishes the rhTNF-alpha and ATP-induced effects on tumour growth by maintaining high GSH levels in the cancer cells. TNF-induced mitochondria GSH depletion appears critical in the cascade of events that lead to cell death.
Departamento de Fisiología, Universidad de Valencia, Facultad de Medicinia, Valencia, Spain.
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Obrador
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Navarro
J
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Mompo
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Asensi
J A
JA
Pellicer
J M
JM
Estrela
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000473:pathology* / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000633:toxicity; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D005978:Glutathione; D019803:Glutathione Disulfide