Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear hormone receptors which play key roles in the differentiation and lipid metabolism of adipocytes. Recent data frequently indicated that PPAR ligands are also implicated in the growth inhibition, differentiation and apoptosis induction of several human cancers with diverse tissues. We previously showed that Pioglitazone (PGZ), a specific PPARgamma ligand and a member of the approved thiazolidinedione (TZD) class of anti-diabetic drugs, inhibited growth and induced apoptosis of human ALL cell lines including Ph-positive ALL cells (Zang et. al., Leukemia Research, 28:387, 2004). In this study, effects of a novel dual ligand specific for PPARalpha/gamma, TZD18 (MERCK, NJ, USA), on Ph-positive ALL cell lines, BV173, SD1 and Sup-B15 were examined. We noted that treatment of these cells with TZD18 resulted in growth inhibition in a dose-dependent manner which was associated with a G1 to S cell cycle arrest. This growth inhibition was much stronger than that of PGZ. However, this effect seemed not to be meditated through activation of PPARalpha or PPARgamma, since antagonists of PPARalpha or gamma could not reverse it. By studying the key regulators of cell cycle progression, we found that the expression of the cyclin dependent kinase inhibitor (CDKI) p27kip1, but not that of p21cip1, was enhanced whereas the expression of c-myc, cyclin D2, and cyclin dependent kinase 2 and 4 (CDK2 and CDK4) was decreased when these cells were treated with TZD18. Therefore, upregulation of p27kip1 and downregulation of cyclin Ds and CDKs may account for the G1 cell cycle arrest. Furthermore, a remarkable apoptosis induction was found in Ph-positive ALL cells treated with this dual ligand as measured by cell-death ELISA. No obvious alteration of bcl-2 levels but an upregulation of bax were observed in apoptotic cells. An activation of caspase-8 and caspase-9 by this ligand was also noticed. Of clinical importance, TZD18 enhanced the cytotoxic effect of Imatinib, a specific therapeutic agent for Ph-positive ALL. Overall, our findings strongly suggest that TZD18 may offer a new therapeutic agent for treatment of Ph-positive ALL in an adjuvant setting. (This study was supported by grants from Deutsche Jose Carreras Leukaemie-Stiftung and Deutsche Forschungsgemeinschaft to EE)
Apoptosis Induction, Cell Cycle Arrest and in Vitro Anticancer Activity of Gonothalamin in a Cancer Cell Lines