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- W2227063985 abstract "AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA5612 Despite of progress in therapy of CML with imatinib, resistances during treatment frequently occur and remain a therapeutic challenge. In this study, we investigated the activity of two novel dual ligands specific for peroxisome proliferator-activated receptor α and γ (PPARα/γ), TZD18 and compound 48 (C48), against CML cell lines. Culture of CML cell lines, both imatinib-sensitive (K562, KU812 and KCL22) and -resistant (K562sr, KU812sr and KCL22sr), with TZD18 or C48 resulted in growth inhibition in a dose- and time-dependent manner without obvious toxicities on normal CD34 positive hematopoietic stem cells as assessed by clonogenic assay. The observed inhibition was much stronger than that either of conventional PPARγ ligand, pioglitazone (PGZ) or PPARα ligand, WY14,643. However, these effects seemed not to be mediated by activation of either PPARα or γ receptors, since antagonists for PPARγ and/or PPARα could not reverse these inhibitions. G0/G1 cell cycle arrests have been observed after exposure to TZD18 or C48 indicating that inhibition of cell cycle progression may account for the observed growth inhibition. Western blot analysis of cell cycle regulators confirmed these results, namely, expression of cyclin dependent kinase (CDK) inhibitor p27kip1 was enhanced, whereas levels of cyclin E, cyclin D2 and CDK 2 were decreased when these cells were treated with either TZD18 or C48.Recent published data indicates that autocrine secretion of GM-CSF is crucial for growth and imatinib resistance of CML cells. We found now, for the first time, that both TZD18 and C48 reduced the secretion of GM-CSF significantly in both imatinib-sensitive and -resistant CML cells suggesting that interference of autocrine growth regulation by GM-CSF may be one of the mechanisms responsible for PPARα/γ ligands induced growth inhibition in CML cells.Finally, of more clinical importance, these ligands enhanced either additively or synergistically the anticancer-effects of imatinib in both imatinib-sensitive and -resistant cells.Overall, our findings clearly suggest that these PPARα/γ ligands, alone or in combination with imatinib, may have potential clinical application in treatment of CML in an adjuvant setting either before or after development of imatinib resistance." @default.
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- W2227063985 date "2007-05-01" @default.
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- W2227063985 title "Novel dual PPARα/γ ligands, TZD18 and compound 48, as growth inhibitors of CML cell lines" @default.
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