Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARα/γ ligand TZD18

Abstract

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 proliferatoractivated 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 G 1 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) p27 kip1 , but not that of p21 cip1 , was enhanced, whereas that of c-Myc, cyclin E, cyclin D2, and cyclindependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with TZD18 (10 or 20 M). 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-B DNAbinding 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. IntroductionAlthough significant progress has been made in the treatment of acute lymphocytic leukemia (ALL), the prognosis for patients with Philadelphia chromosome-positive (Ph ϩ )/Bcr-Abl ϩ adult ALL is still very poor. After first remission, allogeneic stem cell transplantation is the treatment of choice. However, most patients are not eligible for this therapy because of advanced age or lack of a suitable stem cell donor (for reviews, see Redaelli et al 1 and Bassan et al 2 ). Imatinib (Gleevec, previously known as STI571 and CGP57148), the selective tyrosine kinase inhibitor, displayed pronounced antileukemic activity in Ph ϩ chronic myeloid leukemia (CML) and ALL. It is used after allogeneic stem cell transplantation and is recommended for relapsed or refractory Ph ϩ ALL as salvage therapy to facilitate subsequent transplantation. 3 However, quick emergence of resistance to this agent is a major problem in the treatment of patients with Ph ϩ leukemia. Another major obstacle to imatinib-based therapies is the persistence of Ph ϩ cells despite the application of imatinib. Based on these arguments, the development of novel therapeutic a...

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

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“…Furthermore, it is well documented that activation of mouse and human PPARa often results in opposite physiological effects in the liver. 12,14 In humans, PPARa-specific agonists have been recently reported to have antitumor effects in a number of various cancer types such as acute myeloid leukemia, [15][16] chronic lymphocytic leukemia 17 and malignant tumors of the ovary, 18 liver, 19 skin, breast and lung. 20 Recently, fenofibrate was found to be the most potent drug among all of the fibrates in inhibiting the growth of various cell lines derived from melanoma, lung carcinoma, glioblastoma and fibrosarcoma in a xenograft mouse model.…”

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

“…Western blot analysis was performed as described previously. 38 Antibodies against p-AKT (S473), p-AKT (T308) and AKT were from Cell Signaling Technology (New England Biolabs, Frankfurt am Main, Germany); antibody against ß-Actin was from Santa Cruz Biotechnology (Heidelberg, Germany).…”

Impaired cervical homeostasis upon selective ablation of RXRα in epithelial cells

“…One is the extrinsic pathway that is triggered by ligation of cell death receptors leading to activation of Caspase 8. The other is the intrinsic pathway in which the bcl-2 superfamily and mitochondria are involved (Liu et al, 2006). In this case, decrease in the expression of antiapoptotic Bcl-2 protein or an increase in the level of proapoptotic Bax protein disrupts the mitochondrial membranes and releases proapoptotic proteins leading to activation of Caspase 9, as we have observed in cervical epithelium of RXRa mutant mice (Fig.…”

“…As we mentioned, Bcl-2 promotes cell survival, whereas Bax promotes cell death (Adams and Cory, 1998), and it is known that the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus (Adams and Cory, 1998;Liu et al, 2006;Thomas et al, 1996). Thus, the increase in bax gene expression and the decrease in bcl-2 gene expression observed after RXRa ablation should dramatically increase cell death.…”