Superoxide anion inhibits drug-induced tumor cell death

Intracellular superoxide (O-2(.-)) was manipulated in M14 melanoma cells by overexpression or repression of Cu/Zn SOD using a tetracycline-inducible expression system. Scavenging intracellular O-2(.-) increased tumor cell sensitivity to daunorubicin, etoposide, and pMC540, whereas expression of the antisense SOD mRNA significantly decreased cell sensitivity to drug treatment. Whereas Cu/Zn SOD overexpressing cells exhibited higher activation of the executioner caspase 3 upon drug exposure, caspase 3 activation was significantly lower when Cu/Zn SOD was repressed by antisense expression. These data show that intracellular O-2(.-) regulates tumor cell response to drug-induced cell death via a direct or indirect effect on the caspase activation pathway. (C) 1999 Federation of European Biochemical Societies.