Afatinib increased the sensitivity of both imatinib sensitive

susceptible to siRNA mediated degradation than medium and high abundant transcripts. Surprisingly, we found that co administration of BCRABL siRNA with imatinib or nilotinib resulted in enhanced inhibition Afatinib 439081-18-2 of cell growth and BCR ABL gene expression in 32Dp210 cells, including cells with the T315I mutation, which are highly resistant to imatinib and nilotinib. This might be the result of effective modulation by a breakpoint specific siRNA. Consistent with our findings it was previously reported that transfection with BCR ABL specific siRNA and imatinib resistant CML cell lines to imatinib.14 Furthermore, Baker et al. showed that the IC50 of imatinib was 3 fold lower in K562 cells transfected with synthetic or recombinant generated BCR ABL siRNA enabling imatinib to efficiently inhibit the high levels of BCR ABL protein found in these cells.
29 Complex signal transduction pathways are also involved in controlling the proteolysis of potential BCR ABL effectors that may be responsible for some features of BCRABL transformed cells such AZD1480 as deregulated cellular proliferation and apoptosis control through effects on multiple intracellular signaling pathways, including the Ras, phosphatidylinositol 3 kinase, JAK STAT, and NF ?B pathways.30 For example, Perrotti et al. found that the levels of TLS/FUS, an RNA/DNA binding protein involved in transcriptional and post transcriptional regulation of gene expression, are markedly increased in growth factordependent hematopoietic cell lines ectopically expressing BCR ABL and in CML blast crisis bone marrow cells.
31 In addition to regulating gene expression at the transcriptional level, it is increasingly clear that BCR ABL is also involved in post transcriptional regulation via shuttling of heterogeneous nuclear ribonucleoproteins. These proteins play an important role in the control of pre mRNA processing, nuclear mRNA export, and translation.32 Notably, the inhibitory effect on intracellular p Tyr, measured by flow cytometry, declined significantly in the resistant 32Dp210 Thr315Ile cells after treatment with high doses of imatinib or nilotinib or transfection with BCR ABL siRNA or the co administration of siRNA with imatinib or nilotinib in comparison with that of mismatched siRNA or nonmanipulated controls.
Moreover, the inhibitory effect on p Crkl was significantly correlated with siRNA treatment and with co treatment with BCR ABL siRNA and imatinib or nilotinib. The tyrosine kinase activity of BCRABL constitutively induces the phosphorylation of a large panel of proteins, activating multiple signaling pathways responsible for protection against apoptosis, stimulation of growth factor independent proliferation, and alterations of cellular adhesion. P Crkl, a BCR ABL adaptor protein, serves as a surrogate for BCR ABL kinase activity in vivo.33 Our data on p Crkl and p Tyr support the efficacy of BCR ABL siRNA transfection in vitro and validate our above described findings on cell growth and BCR ABL expression in mutated 32Dp210 cells. Furthermore, we found that combining BCRABL siRNA transfection with imatinib or nilotinib had additive effects on induction of apoptosis and inhibition of proliferation of 32Dp210 cell lines, including mutated 32Dp210 His

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