Enhanced differentiation of HL-60 leukemia cells to macrophages induced by ciprofibrate

Bronfman, Miguel; Ponce, Carolina; Rojas, Sandra; Roth, Alejandro D.; Loyola, Gloria; Vollrath, Valeska; Chianale, José

doi:10.1016/s0171-9335(98)80109-x

Cited by 10 publications

(8 citation statements)

References 21 publications

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Section: Introductionmentioning

confidence: 83%

“…12,37,38 However, to date, reports of PPAR␣ expression in hematopoietic cells are limited to human myeloblastic leukemia cell line HL-60 23,39 and murine lymphocytes. 40 We have shown in this study that human Ph ϩ ALL cell lines also express PPAR␣.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21] Furthermore, fibrates cause growth arrest by regulating cell cycle-related factors and induce the monocytic differentiation of HL-60 cells. 22,23 These data indicate that this subtype of the PPAR family could also have anticancer activities.TZD18 ( Figure 1A) is one of a series of compounds synthesized by Merck (Rahway, NJ) that can specifically bind and activate PPAR␣ and PPAR␥. In addition to its specificity to both these receptors, this compound has pharmacokinetic parameters superior to those of other members of this series: high bioavailability, high-dose normalized AUC, and relatively low clearance.…”

mentioning

confidence: 83%

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

Liu

Zang

Fenner

et al. 2006

Blood

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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...

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

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

Liu

Zang

Fenner

et al. 2006

Blood

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“…Other PPAR α activators, including putative endogenous ligands such as fatty acids, induce differentiation and inhibit proliferation in keratinocytes [89]. The PPAR α ligand, ciprofibrate induces differentiation of HL-60 cells and its effect is potentiated by phorbol 12-myristate 13-acetate (TPA) [90]. Benzafibrate induces differentiation of HL-60, U937, and K562 cells [91].…”

Section: The Role Of Ppar Ligands In Affecting Cell Proliferation mentioning

confidence: 99%

The Role of PPAR Ligands in Controlling Growth‐Related Gene Expression and their Interaction with Lipoperoxidation Products

Barrera¹,

Toaldo²,

Pizzimenti³

et al. 2008

PPAR Research

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Peroxisome proliferators-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three PPAR isoforms (α, γ and β/δ) have been found to play a pleiotropic role in cell fat metabolism. Furthermore, in recent years, evidence has been found regarding the antiproliferative, proapoptotic, and differentiation-promoting activities displayed by PPAR ligands, particularly by PPARγ ligands. PPAR ligands affect the expression of different growth-related genes through both PPAR-dependent and PPAR-independent mechanisms. Moreover, an interaction between PPAR ligands and other molecules which strengthen the effects of PPAR ligands has been described. Here we review the action of PPAR on the control of gene expression with particular regard to the effect of PPAR ligands on the expression of genes involved in the regulation of cell-cycle, differentiation, and apoptosis. Moreover, the interaction between PPAR ligands and 4-hydroxynonenal (HNE), the major product of the lipid peroxidation, has been reviewed.

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“…[13][14][15][16] PPARα ligands have been shown to inhibit growth and induce either apoptosis or differentiation of glial, 17 breast cancer cell lines 18 and acute myeloid leukaemia cell lines. 19,20 TZD18 (Fig. 1A) is one of a series of compounds synthesized by Merck (USA) which can specifically bind and activate both PPARα and PPARγ.…”

Section: Introductionmentioning

confidence: 99%

Dual PPARα/γ Ligand TZD18 Either Alone or in Combination with Imatinib Inhibits Proliferation and Induces Apoptosis of Human CML Cell Lines

Zang

H²,

Waechter³

et al. 2006

Cell Cycle

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Enhanced differentiation of HL-60 leukemia cells to macrophages induced by ciprofibrate

Cited by 10 publications

References 21 publications

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

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

The Role of PPAR Ligands in Controlling Growth‐Related Gene Expression and their Interaction with Lipoperoxidation Products

Dual PPARα/γ Ligand TZD18 Either Alone or in Combination with Imatinib Inhibits Proliferation and Induces Apoptosis of Human CML Cell Lines

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