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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3683-3692.
Prepublished online as a Blood First Edition Paper on January 10, 2006; DOI 10.1182/blood-2005-05-2103.
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NEOPLASIA
Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPAR / ligand TZD18
Hongyu Liu,
Chuanbing Zang,
Martin H. Fenner,
Dachuan Liu,
Kurt Possinger,
H. Phillip Koeffler, and
Elena Elstner
From the Division of Hematology/Oncology, School of Medicine (Charité), Humboldt University, Berlin, Germany; and the Division of Hematology/Oncology, Cedars-Sinai Medical Center/University of California at Los Angeles, School of Medicine, Los Angeles, CA.
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  and  (PPAR/) 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 G1 cell cycle arrest. This effect was much stronger than that mediated by the PPAR ligand pioglitazone (PGZ), which also belongs to the thiazolidinediones (TZD) class of ligands. However, it may not be mediated through PPAR or PPAR activation because antagonists of PPAR and PPAR 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) p27kip1, but not that of p21cip1, 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 µM). Therefore, the up-regulation of p27kip1 and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G1 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- B 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.
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[Abstract]
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