The mechanism by which Sorafe nib inhibits Akt phosphorylation remains uncertain. Sorafenib Decreased levels of pAkt might be caused by inhibiting different upstream tyrosine kinases, as Sorafenib has also a potent activity against VEGFR, c Inhibitors,Modulators,Libraries Kit, c Raf and B Raf. Expression of VEGFR 2 has been demonstrated in haematopoetic stem cells. After ligand binding of VEGFR 2 and following autophosphorylation, the Ras Raf Mek Erk pathway and the PI3K Akt signaling cas cade are activated. In this context, we presume a cross talk between both pathways that provide Akt inhi bition after Sorafenib treatment in ALL cells. Recent studies described an interaction between MAPK and mTOR pathway. These findings support our hypothesis that Sorafenib induced inhibition of PI3K Akt mTOR as a result of blocking upstream several tyr osine kinases as well as Ras Raf Erk pathway.
Further, it is known that Sorafenib inhibits FMS like tyrosine kinase 3. This receptor tyrosine kinase is mainly expressed in early myeloid and lymphoid progenitor cells and activates PI3K and Ras signal transduction cascades. Internal tandem duplica tion insertions in the juxtamembrane domain of FLT3 leads to constitutive activation of this receptor. FLT3 ITD Inhibitors,Modulators,Libraries are common in AML whereas this mutation occurs much less frequently in ALL. Inhibitors,Modulators,Libraries Additionally, it has been reported that mixed lineage leukemia gene rearrangement and hyperdiploid patients offer point mutations in the activation loop in the tyrosine kinase domain of FLT3. This mutation results in ligand independent receptor dimerization, phosphorylation and constitutive activation of downstream signalling pathways and is more frequent in ALL.
SEM and Inhibitors,Modulators,Libraries RS4.11 are precursor B ALL cell lines and carry the t MLL AF4 fusion protein. However, both cell lines are negative for FLT3 ITD. In order to enhance antiproliferative effects, combina tion of cytostatic drugs is commonly a reasonable approach. Successful combination therapy might enhance the impact of inhibitors, allowing lower doses of cyto Inhibitors,Modulators,Libraries static drugs and thereby reducing side effects. Different studies in patients with melanoma, hepatocellular carci noma or non small cell lung cancer suggest that Sorafe nib has the potential to be combined with a variety of cytotoxic drugs and targeted agents. Here, we treated cells with 0. 73 uM or 7. 3 uM Sorafenib in combi nation with sub IC50 concentrations of cytarabine, dox orubicin and the mTOR inhibitor RAD001.
Our studies demonstrate directly that the in vitro effect of co treatment with Sorafenib and cytostatics is Bliss synergistic in B ALL cells regarding proliferation, apoptosis and necrosis as well. These results indicate that simultaneous application of Sorafenib with the tested conventional cytotoxic drugs might lead to synergistic impact, exceeding the expected pure additive effect of individual compounds with inde pendent action.