3 h, indicating that glucocorticoid resistance The LLC is not NVP-LAQ824 LAQ824 due to a variation in the cellular Ren inclusion of dexamethasone-induced or GR Ver Changes in gene transcription. As n Chstes we examined whether dasatinib sensitivity to dexamethasone in primary Ren CLL improve seven samples and peripheral blood lymphocytes isolated from a patient with a flow cell lymphoma mantle. We found that dasatinib significantly the response to dexamethasone therapeutically relevant concentrations of 10  improved 10  M. In 72 h erh Ht dasatinib response to dexamethasone by more than two size Enordnungen and induces cell death more than 50%. The effect of MEC1 cells was Similar cell death as dasatinib also improved approx Hr twice after 24 h of treatment with increasing concentrations of dexamethasone.
Furthermore, the combination of the two agents has more than tripled the amount of dead cells from apoptosis. For contr L is the potential nonspecific dasatinib also CLL cells treated with a combination of dexamethasone and the Src inhibitor PP2 and the phosphopeptide EGQYEEIP, where the asterisk denotes a phosphorylated tyrosine residue. This peptide is derived from hamster polyomavirus middle T antigen binds with high affinity t to other Src Lck proteins.37, 38 As compared to the Lck SH2 Dom ne is required for TCR signaling inhibit these peptides Lck SH2 39 , 40 induced by blocking ligand interactions. PP2 and peptide YEEI t had a certain degree of activity As single agents, but also improved Zellabt Tion in response to dexamethasone.
We also have the connection in 1120 BIBF has about a size Enordnung h Here selectivity t for Lck other Src family kinases.41 BIBF Similar results, also shows the importance of Lck inhibition. It S we close that inhibition of Lck significantly improved the sensitivity of t to dexamethasone in a model of malignant lymphocytes Who is relatively unresponsive to corticosteroid therapy. Discussion Here we report that Lck cells from apoptosis induced by glucocorticoids protect Of. T cells in glucocorticoid-sensitive Of, Lck is down-regulated by dexamethasone, inhibit the activation of TCR and signaling. Because TCR activation antagonizes apoptosis induced by glucocorticoids Of, 9, 12 we thought that the inhibition of Lck k Nnte confer sensitivity to dexamethasone.
We have shown that the inhibition of Lck or RNAi molecule inhibitor dasatinib small verst Markets apoptosis by glucocorticoid Induced cells in lymphoid Of found, especially in prime Ren Leuk Miezellen are partially resistant to dexamethasone. CLL is a clinically relevant model of malignant lymphocytes Because glucocorticoid Synthetics, such as prednisone and dexamethasone, are widely used in combination with other chemotherapeutic agents for the treatment of CLL and aggressive use. Previous studies have shown that glucocorticoids Rapidly inhibit Lck one nongenomic mechanism with interactions between the ligand bound GR and TCR signaling complex.22, 23 In addition, it has been shown that dexamethasone redistributed Lck in Fl S lipid after T-cell activation, whereby its activity .19 Although these studies clearly demonstrate that glucocorticoids the Lck and other Src family kinases inhibited by various mechanisms.