The combination compared to the use of BCR ABL siRNA alone. This suggests that BCR ABL siRNA and tyrosine kinase inhibitors affect BCR ABL positive cells by modulating or transforming genes via different pathways promising additive BIBW2992 Tomtovok selective antitumor activity. Ong et al. recently reported that mammalian target of rapamycin dependent pathways are constitutively activated in BCR ABL transformed cells.34,35 These studies raised the possibility that regulation of mTOR may be a mechanism by which BCR ABL promotes cell growth and survival of leukemic cells, but the mTOR effectors mediating such responses are not fully understood.
Tyrosine kinase inhibitors, such as imatinib and nilotinib, target and block engagement of the mTOR pathway in BCR ABL expressing cells. Such effects of BCR ABL kinase inhibitors are observed in cells AZD7762 transformed by imatinib resistant BCR ABL kinase mutants, establishing that the mTOR/p70 S6K pathway plays a critical role in promoting the leukemogenic effects of BCR ABL.36 Recently, Ohba et al. demonstrated, by microarray analysis of K562 cells, that there is cross talk between siRNA interference and BCR ABL oncogeny and found that the expression of approximately 250 genes was changed. RNA interference of BCR ABL was accompanied by decreased expression of various proto oncogenes, growth factors, factors related to kinase activity, and factors related directly to cell proliferation.
Several factors responsible for the development of apoptosis increased, including STATinduced STAT inhibitors and apoptosis related RNA binding proteins.37 Furthermore, Zhou et al. demonstrated that Adelson helper integration site 1 is a novel BCR ABL interacting protein that is also physically associated with JAK2. This AHI 1 BCR ABL JAK2 complex seems to modulate BCR ABL transforming activity and the response/resistance of CML stem/progenitor cells to tyrosine kinase inhibitors through an interleukin 3 dependent BCRABL and JAK2 STAT5 pathway.38 In experiments focused on cell cycle analysis, the cell cycle distribution and apoptotic responses induced by BCR ABL siRNA, tyrosine kinase inhibitors or co treatment with BCRABL siRNA and tyrosine kinase inhibitors seemed to differ.
We found that the effects of transfection with BCR ABL siRNA depend on cell cycle arrest in the early S phase rather than on the disruption of the G2 checkpoint and on an increased apoptotic distribution with DNA fragmentation. By adding imatinib or nilotinib to BCRABL siRNA treatment these effects increased approximately 1.3 fold. This strongly suggests that dual inhibition of BCR ABL by BCR ABL siRNA combined with nilotinib additively enhances 32Dp210 cytotoxicity and apoptosis. In K562 cells, imatinib enhanced the inhibitory effect of radiation on proliferation of K562 cells and decreased the G2 phase content due to an efficient arrest in the S phase.39 Mazzacurati et al. found that imatinib also induces growth arrest by activating the Chk2 Cdc25A Cdk2 axis, a pathway complementary to p53 in the activation of the G1/S cell cycle checkpoint, involved in cell fate decisions such as regulation of cell cycle progression, DNA repair and survival rather than apoptosis.40 Ot
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