|
|
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.
 Previous Article | Next Article 
Submitted May 25, 2005
Accepted December 22, 2005
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 P Koeffler, and Elena Elstner*
Division of Hematology/Oncology, School of Medicine (Charite), Humboldt University, Berlin, Germany
Division of Hematology/Oncology, Cedars-Sinai Medical Center/University of California L.A., School of Medicine, Los Angeles, CA, USA
* Corresponding author; email: elena.elstner{at}charite.de.
Treatment of adult Philadelphia chromosome-positive lymphocytic leukemia is rarely successful. We reported here the effects of TZD18 (MERCK, NJ, USA), 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 which was associated with a G1 cell cycle arrest. These effects were much stronger than those mediated by the PPAR ligand Pioglitazone (PGZ) which belongs also to the Thiazolidinediones (TZD) class of ligands. However, this effect may not be mediated through PPAR and PPAR activation, since antagonists of PPAR and/or PPAR could not reverse this effect. Study of the key regulators of cell cycle progression by Western blot showed 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 E, cyclin D2, cyclin dependent kinase 2 and 4 (CDK-2, and CDK-4) were decreased when these cells were treated with TZD18 (10 or 20 µM). Therefore, upregulation of p27kip1, and downregulation of cyclin Ds, CDK-2 and 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 upregulated in these TZD18-treated cells. An activation of both caspase-8 and -9 by TZD18 was also noticed. 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 PhPh+- lymphocytic leukemia.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Zang, H. Liu, J. Bertz, K. Possinger, H. P. Koeffler, E. Elstner, and J. Eucker
Induction of endoplasmic reticulum stress response by TZD18, a novel dual ligand for peroxisome proliferator-activated receptor {alpha}/{gamma}, in human breast cancer cells
Mol. Cancer Ther.,
August 1, 2009;
8(8):
2296 - 2307.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-J. Liu, Yan-Xu, Y. Zhang, R.-Z. Xiao, and D.-J. Lin
Peroxisome Proliferator-Activated Receptor {gamma} (PPAR-{gamma}) Agonist Rosiglitazone (RGZ) Inhibits HL-60 Cell Growth by Induction of Apoptosis
Lab Med,
May 1, 2009;
40(5):
297 - 302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
