Arsenic trioxide cytotoxicity in steroid and chemotherapy-resistant myeloma cell lines: enhancement of apoptosis by manipulation of cellular redox state.

PURPOSE We investigated the ability of pretreatment with buthionine sulfoximine (BSO) to overcome a priori resistance to arsenic trioxide (As(2)O(3)) in multiple myeloma (MM) cells and determine whether this was through an apoptotic mechanism that involves changes in the cellular redox state. EXPERIMENTAL DESIGN Using a panel of dexamethasone and chemotherapy-resistant MM cell lines, we examined growth inhibition, induction of apoptosis, and changes in the redox state by As(2)O(3) alone or after preincubation with BSO. RESULTS Whereas the sensitive cell lines showed 100% killing at 0.5 micromol/liter of As(2)O(3), the resistant cell lines required BSO pretreatment to achieve 100% killing at this dose. By comparison, the peak As(2)O(3) plasma concentration in acute promyelocytic leukemia in patients successfully treated was 5-7 micromol/liter with rapid decline to a sustained level of 1-2 micromol/liter. We demonstrated that BSO and As(2)O(3)-induced cytotoxicity was attributable to induction of apoptosis accompanied by activation of the death signals: caspases 3, 8, and 9. CONCLUSIONS We have demonstrated that growth inhibition of highly resistant MM cell lines by As(2)O(3) is facilitated by BSO and that this effect is accompanied by caspase activation, presumably leading to activation of apoptosis. These data indicate that steroid and chemotherapy-resistant MM cell lines can be overcome by manipulation of the cellular redox state. Because BSO and As(2)O(3) can be used at clinically relevant concentrations, we believe that our observations may have important implications for the treatment of MM.