Troglitazone inhibits cell growth and induces apoptosis of B-cell acute lymphoblastic leukemia cells with t(14;18)

Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a member of the nuclear receptor superfamily, has been detected in several human leukemia cells. Recent studies reported that PPAR gamma ligands inhibit cell proliferation and induce apoptosis in both normal and malignant B-lineage cells. We investigated the expression of PPAR gamma and the effects of PPAR gamma ligands on UTree-O2, Bay91 and 380, three B-cell acute lymphoblastic leukemia (B-ALL) cell lines with t(14;18), which show a poor prognosis, accompanying c-myc abnormality. Western blot analysis identified expression of PPAR gamma protein and real-time PCR that of PPAR gamma mRNA on the three cell lines. Troglitazone (TGZ), a synthetic PPAR gamma ligand, inhibited cell growth in these cell lines in a dose-dependent manner, which was associated with G(1) cell cycle arrest and apoptosis. We also found this effect PPAR gamma independent since PPAR gamma antagonists failed to reverse this effect. We assessed the expression of c-myc, an apoptosis-regulatory gene, since c-myc abnormality was detected in most B-ALL cells with t(14;18). TGZ was found to dose-dependently downregulate the expression of c-myc mRNA and c-myc protein in the three cell lines. These results suggest that TGZ inhibits cell growth via induction of G, cell cycle arrest and apoptosis in these cell lines and that TGZ-induced apoptosis, at least in part, may be related to the downregulation of c-myc expression. Moreover, the downregulation of c-myc expression by TGZ may depend on a PPAR gamma-independent mechanism. Further studies indicate that PPAR gamma ligands may serve as a therapeutic agent in B-ALL with t(14;18). Copyright (c) 2006 S. Karger AG, Basel