Dithiothreitol enhances arsenic trioxide-induced apoptosis in NB4 cells

Recently, arsenic trioxide (As2O3) was reported to induce clinical remissio n in patients with acute promyelocytic leukemia. Modulation of protein phos phorylation by binding to the vicinal thiols has been suggested as a possib le mechanism. We found that phenylarsine oxide, a strong vicinal thiol-bind ing agent, neither induced nuclear fragmentation or DNA laddering nor incre ased caspase activity in NB4 cells; however, As2O3 and a weak thiol-binding agent, dimethylarsinic acid, did increase activity. Dithiothreitol (DTT) e ffectively suppressed the phenylarsine oxide-inhibited cellular reductive c apacity, but unexpectedly, enhanced As2O3-induced apoptosis in NB4 cells. A s2O3-induced and As2O3-plus-DTT-induced apoptosis in NB4 cells was modulate d by oxidant modifiers, but not by nitric oxide synthase inhibitors. These results demonstrate that DTT, a dithiol agent and known antidote for trival ent inorganic arsenic, enhances the toxicity of As2O3, thereby opening a ne w research direction for the mechanisms of arsenic toxicity and perhaps als o helping in the development of new therapeutic strategies for treating leu kemias.