Affiliations: Departamento de Fisiología, Universidad de Valencia, Facultad de Medicina, Av. Blasco Ibañez 17, 46010 Valencia, Spain
Note: [] To whom correspondence should be addressed: Dr. José M. Estrela, Departamento de Fisiología, Facultad de Medicina, Av. Blasco Ibañez 17, 46010 Valencia, Spain. Tel.: 6 3864646; Fax: 6 3864642; E‐mail: Jose.M.Estrela@ uv.es.
Abstract: 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, O_{2}\mathbin{\hbox{\tenbsy\char"01}}^- 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 mitochondrial GSH depletion appears critical in the cascade of events that lead to cell death.
Journal: Biofactors, vol. 8, no. 1-2, pp. 23-26, 1998
