title: Dithiothreitol enhances arsenic trioxide-induced apoptosis in NB4 cells.
abstract: 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.
authors.affiliation: Institute of Zoology, Academia Sinica, Taipei, Republic of China.
authors.forename: J R
authors.initials: JR
authors.lastname: Gurr
authors.forename: D T
authors.initials: DT
authors.lastname: Bau
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Lynn
authors.forename: K Y
authors.initials: KY
authors.lastname: Jan
mesh_terms: D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004229:Dithiothreitol / Q000494:pharmacology*; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001152:Arsenicals; D006131:Growth Inhibitors; D010087:Oxides; D017382:Reactive Oxygen Species; D020169:Caspases; D000077237:Arsenic Trioxide; D004229:Dithiothreitol