TY - JOUR T1 - Dithiothreitol Enhances Arsenic Trioxide-Induced Apoptosis in NB4 Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 102 LP - 109 DO - 10.1124/mol.56.1.102 VL - 56 IS - 1 AU - Jia-Ran Gurr AU - Da-Tian Bau AU - Fount Liu AU - Shugene Lynn AU - Kun-Yan Jan Y1 - 1999/07/01 UR - http://molpharm.aspetjournals.org/content/56/1/102.abstract N2 - Recently, arsenic trioxide (As2O3) was reported to induce clinical remission in patients with acute promyelocytic leukemia. Modulation of protein phosphorylation by binding to the vicinal thiols has been suggested as a possible mechanism. We found that phenylarsine oxide, a strong vicinal thiol-binding agent, neither induced nuclear fragmentation or DNA laddering nor increased caspase activity in NB4 cells; however, As2O3 and a weak thiol-binding agent, dimethylarsinic acid, did increase activity. Dithiothreitol (DTT) effectively suppressed the phenylarsine oxide-inhibited cellular reductive capacity, but unexpectedly, enhanced As2O3-induced apoptosis in NB4 cells. As2O3-induced and As2O3-plus-DTT-induced apoptosis in NB4 cells was modulated by oxidant modifiers, but not by nitric oxide synthase inhibitors. These results demonstrate that DTT, a dithiol agent and known antidote for trivalent inorganic arsenic, enhances the toxicity of As2O3, thereby opening a new research direction for the mechanisms of arsenic toxicity and perhaps also helping in the development of new therapeutic strategies for treating leukemias. ER -