Treatment of adult
Philadelphia chromosome-positive
lymphocytic leukemia is rarely successful. We report here the effects of
TZD18, a novel dual
ligand specific for
peroxisome proliferator-activated receptor alpha and gamma (
PPARalpha/gamma) on Ph(+)
lymphocytic leukemia cell lines BV173,
SD1, and SupB-15. Exposure of these cells to
TZD18 resulted in growth inhibition in a dose- and time-dependent manner that was associated with G(1) cell cycle arrest. This effect was much stronger than that mediated by the
PPARgamma ligand pioglitazone (PGZ), which also belongs to the
thiazolidinediones (TZD) class of
ligands. However, it may not be mediated through
PPARgamma or
PPARalpha activation because antagonists of
PPARgamma and
PPARalpha cannot reverse it. Study of the key regulators of cell cycle progression by Western blot analysis showed that the expression of the
cyclin-dependent kinase inhibitor (CDKI) p27(kip1), but not that of p21(cip1), was enhanced, whereas that of c-Myc,
cyclin E,
cyclin D2, and
cyclin-dependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with
TZD18 (10 or 20 microM). Therefore, the up-regulation of p27(kip1) and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G(1) cell cycle arrest. Furthermore, a remarkable induction of apoptosis was observed in the cells treated with this dual
ligand. No obvious alteration of bcl-2
protein level occurred, but bax was up-regulated in these TZD18-treated cells. Activation of
caspase 8 and
caspase 9 by
TZD18 was also observed. Importantly,
NF-kappaB DNA-binding activity was markedly decreased by the
TZD18 treatment. In addition,
TZD18 enhanced the growth inhibitory effect of
imatinib, a specific
tyrosine kinase inhibitor therapeutically used in the treatment of Ph(+)
leukemia. Overall, our findings strongly suggest that
TZD18 may offer a new therapeutic approach to aid in the treatment of Ph(+)
lymphocytic leukemia.