The GSK 3B chemical SB216763 completely blocked ATO induced Mcl 1 reduction, but only partly inhibited ATO induced apoptosis. The degrees of p ERK were diminished by ATO treatment at a concentration of 1 uM. Since the quantities of Mcl 1 weren’t decreased by ATO at 1 uM, the inhibition of ERK activity seems to be an early event resulting in Mcl 1 reduction by reducing its phosphorylation. Therapy with ERK inhibitors, PD184352 and U0126, reduced p Mcl 1 and Mcl 1 degrees. Sorafenib, Imatinib CGP-57148B a Raf inhibitor, reduced the degrees of p MEK and Mcl 1 and acted synergistically with ATO to induce apoptosis in cells. Therapy with sorafenib alone did not somewhat lower p ERK levels which may be due to feedback activation by inhibiting p MEK. It’s been discovered that sorafenib decreases the quantities of Mcl 1 through inhibition of translation. It also is discovered that sorafenib can lower Mcl 1 phosphorylation levels by inhibiting ERK activity. Organism Consequently, it seems that inhibition of both new protein synthesis and Mcl 1 phosphorylation may donate to the combined effects of sorafenib plus ATO in decreasing Mcl 1 levels in NB4 cells. Recently it was unearthed that GSK 3B modulated Mcl 1 degradation by phosphorylating Mcl 1 at sites differing from these phosphorylated by ERK. The activity of GSK 3B is managed by phosphorylation which keeps it in a inactive form. Both ERK and AKT phosphorylate GSK 3B. The degree of p GSK 3B was reduced in NB4 cells after ATO treatment. Since an antibody to check the degrees of phosphorylated Mcl 1 at Ser159 as a result of GSK 3B service is not available, we employed a GSK 3B chemical and GSK 3B siRNA to determine the impact on ATO induced Mcl 1 reduction. Both the GSK 3B chemical SB216763 and GSK 3B siRNA blocked Mcl 1 reduction by ATO. pan Chk inhibitor It is known that GSK 3B phosphorylates Mcl 1 leading to its proteasomal degradation. We discovered that the proteasome inhibitor, MG132, blocked ATO induced Mcl 1 decrease in NB4 cells. These data suggest that the decrease in Mcl 1 levels following ATO treatment is due to two pathways: 1) activation of GSK3B by lowering p ERK and AKT levels which encourages Mcl 1 phosphorylation at Ser159 and destruction and 2) direct inhibition of ERK induced phosphorylation of Mcl 1 at Thr163 which destabilizes Mcl 1. Because silencing Mcl 1 sensitizes ATO induced apoptosis in HL 60 cells, it appears that Mcl 1 plays an important role in protecting cells from ATO induced apoptosis. ERK and AKT inhibitors, sorafenib, PD184352, and LY294002, all lowered the degrees of p GSK 3B and Mcl 1 protein and augmented ATO induced apoptosis. Since treatments with sorafenib, PD184352, or LY294002 somewhat reduced Mcl 1 levels and on their own did not induce apoptosis, the apoptotic effects of combinations of these inhibitors with ATO seem not to be induced due only to decreases in Mcl 1 levels.