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Regulation of tumour cell sensitivity to TNF‐induced oxidative stress and cytotoxicity: Role of glutathione
Author(s) -
Obrador Elena,
Navarro JosÉ,
Mompo Juan,
Asensi Miguel,
Pellicer José A.,
Estrela José M.
Publication year - 1998
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.5520080105
Subject(s) - glutathione , buthionine sulfoximine , oxidative stress , cytotoxicity , programmed cell death , tumor necrosis factor alpha , intracellular , apoptosis , cell growth , necrosis , mitochondrion , chemistry , growth inhibition , pharmacology , biology , biochemistry , in vitro , medicine , endocrinology , enzyme
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)‐α cytoxicity in vitro. Administration of sublethal doses of rhTNF‐α to Ehrlich ascites‐tumour (EAT)‐bearing mice induces oxidative stress (as measured by increases in intracellular peroxide levels, O 2 ·& — generation and mitochondrial GSSG). ATP‐induced selective GSH depletion, when combined with rhTNF‐α 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‐α 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.