Oxidative stress appears to have a central role in the induction of apoptosis following the exposure of cells to a range of cytotoxic insults. The modulation of apoptosis by a diverse range of antioxidants has been reported in many systems. We demonstrate, for the first time, the anti-apoptotic properties of the antioxidant, 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII), in Jurkat T cells subjected to a number of cytotoxic insults. THII was found to inhibit the morphological features of apoptosis in cells treated with the cytotoxic agents camptothecin, actinomycin D and ultraviolet (UV) irradiation. However, THII was unable to inhibit apoptosis induced by anti-Fas IgM. Peroxide and superoxide anion production following UV treatment was monitored, and THII was found to only partially inhibit superoxide anion production. THII was unable to inhibit mitochondrial depolarization in UV, Camptothecin or anti-Fas-treated cells. Further downstream, THII exibited strong inhibition of caspase-3 activation in UV, but not in anti-Fas-treated cells. These results suggest that THII may exert its effects downstream of mitochondrial depolarization, but upstream of caspase-3 activation. (C) 1999 Academic Press.