Arsenic trioxide induces infection remission in acute promyelocytic leukemia patients, but perhaps not in non APL acute k63 ubiquitin myeloid leukemia patients. ATO at therapeutic levels cause APL NB4, but maybe not non APL HL 60, cells to undergo apoptosis through the mitochondrial pathway. The position of anti-apoptotic protein Mcl 1 in ATO induced apoptosis was determined. The levels of Mcl 1 were lowered in NB4, however not in HL 60, cells after ATO therapy through proteasomal degradation. Both GSK3B inhibitor SB216763 and siRNA blocked ATO induced Mcl 1 reduction as well as attenuated ATO induced apoptosis in cells. Silencing Mcl 1 sensitized HL 60 cells to ATO induced apoptosis. Both ERK and AKT inhibitors reduced Mcl 1 levels and increased ATO induced apoptosis in HL 60 cells. Sorafenib, Carcinoid a Raf inhibitor, activated GSK3B by inhibiting its phosphorylation, decreased Mcl 1 levels, and decreased intracellular glutathione levels in HL 60 cells. Sorafenib plus ATO increased ROS generation and apoptosis induction in HL 60 cells and in key AML cells. These indicate that ATO causes Mcl 1 wreckage through activation of GSK3B in APL cells and provide a reason for using ATO in combination with sorafenib for the treatment of non APL AML patients. Arsenic trioxide alone successfully induces remission in acute promyelocytic leukemia patients with the PML RAR fusion protein and is approved for relapsed APL treatment. The induction of partial differentiation and apoptosis is observed to be the mechanism of action of ATO in APL. ATO triggers APL cell apoptosis with a process that is independent of PML RAR degradation, although ATO induced PML RAR degradation occurs during therapy for APL. ATO, like a single agent, has not succeeded in treatment of other types of acute myeloid leukemia. Taking into consideration the minimum toxicity of ATO in APL patients, it has been suggested that ATO might be along with Decitabine clinical trial other agents for AML treatment. Formerly other organizations, and we, are finding that ATO induced apoptosis in APL cells is, at the very least in part, mediated through H2O2 accumulation, which is followed closely by changes in mitochondrial transmembrane permeability, cytochrome c release, and caspase activation. More over, our studies showed that the remarkable sensitivity of APL cells to ATO caused apoptosis, in comparison to cells isolated from other styles of myeloid leukemia such as HL 60 and U937, was correlated with greater H2O2 deposition. Though it has been found that agents such as ascorbic acid, which boost the degrees of H2O2, improved ATO apoptosis induction of non APL malignant cells, a written report mentioned that reactive oxygen species appear not to be required for ATO induced apoptosis. Multiple signaling pathways appear to be governed by ATO in APL cells.