Buthionine sulfoximine enhancement of arsenic trioxide-induced apoptosis in leukemia and lymphoma cells is mediated via activation of c-Jun NH2-terminal kinase and up-regulation of death receptors.

The mechanism of apoptosis induced by treatment with As(2)O(3) alone or in combination with buthionine sulfoximine (BSO) was studied in NB4, U937, Namalwa, and Jurkat cells. As(2)O(3) at concentrations <2 micromol/L induced apoptosis in NB4 cells and Namalwa cells but not in U937 and Jurkat cells. As(2)O(3)-induced apoptosis in NB4 cells and Namalwa cells correlated with increase of H(2)O(2) and caspase activation without activation of c-Jun NH(2)-terminal kinase (JNK). BSO (10 micromol/L) depleted the reduced form of intracellular glutathione without inducing apoptosis but synergized with 1 micromol/L As(2)O(3) to induce apoptosis in all four cell lines. This synergy correlated with JNK activation. Treatment with As(2)O(3) plus BSO, but not with As(2)O(3) alone, increased the levels of death receptor (DR) 5 protein and caspase-8 cleavage. The JNK inhibitor SP600125 inhibited the increase in DR5 protein and attenuated apoptosis induced by treatment with As(2)O(3) plus BSO. These observations suggest that a DR-mediated pathway activated by JNK is involved in apoptosis induced by treatment with As(2)O(3) plus BSO.