Human B Lymphocytes and B Lymphomas Express PPAR-γ and Are Killed by PPAR-γ Agonists

Padilla, Josué; Leung, Edmund; Phipps, Richard P.

doi:10.1006/clim.2001.5181

Cited by 121 publications

(101 citation statements)

References 41 publications

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“…PPARg receptor is expressed in normal and malignant human B cells and PPARg agonists have been reported to induce apoptosis in such B lineage cells [21,22]. We confirmed such studies using the thiazolidinedione PPARg agonist ciglitazone (data not shown).…”

Section: Pparg Receptor and Nf-kb Studiessupporting

confidence: 80%

Preclinical assessment of curcumin as a potential therapy for B‐CLL

et al. 2006

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Curcumin, the principle component of the spice turmeric, has been used as an anti-inflammatory medication in India and China for centuries. Recent studies, predominantly using actively dividing cell lines, have suggested that this compound could be used as a chemopreventative or therapeutic agent for epithelial tumors. As curcumin has been reported to inhibit the NIK/IKK complex, an activity that would be expected to induce apoptosis in B cell malignancies, we sought to determine whether curcumin induces apoptosis in vitro in primary chronic lymphocytic leukemia (B-CLL) cells. Primary leukemic cells were incubated with varying dosages of curcumin, followed by assessment for apoptosis. The role of PPARg or NF-kB signaling in curcumin-induced apoptosis was examined by cotreatment with a PPARg antagonist or EMSA of nuclear NFkB complexes. We also examined whether a clinically achievable concentration of curcumin (1 mM) would augment the apoptotic effects of fludarabine, dexamethasone, vincristine or the PDE4 inhibitor rolipram. In B-CLL cells from 14 patients, curcumin-induced apoptosis with a mean EC 50 of 5.5 mM. In contrast, the EC 50 for whole mononuclear cells from a healthy donor was 21.8 mM. In a 48 hr wash-out time course, curcumin-induced apoptosis was time-dependent, with a substantial reduction in apoptosis observed when curcumin was removed after 5 hr. Curcumin treatment reduced basal nuclear NF-kB levels and 1 mM curcumin augmented both vinca alkaloid and PDE4 inhibitor-induced apoptosis in B-CLL cells. Our studies suggest that curcumin may augment the efficacy of established or experimental therapies for B-CLL. Am. J. Hematol. 82:23-30, 2007. V V C 2006 Wiley-Liss, Inc.

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Section: Pparg Receptor and Nf-kb Studiessupporting

confidence: 80%

Preclinical assessment of curcumin as a potential therapy for B‐CLL

et al. 2006

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“…Human B lymphocytes abundantly express PPAR␥ and are killed by a variety of structurally dissimilar small molecule PPAR␥ agonists (12,41). According to our previous studies and the data reported herein, the EC 50 for cell death induction by PPAR␥ agonists in human B lymphocytes is 2 M for 15d-PGJ 2 and 7 M for ciglitazone (12).…”

Section: A Dn Ppar␥ Does Not Prevent Ppar␥ Agonist-induced Cell Deathsupporting

confidence: 74%

“…We previously reported that both mouse and human normal and malignant B lymphocytes abundantly express PPAR␥ and undergo apoptosis after exposure to both natural and synthetic PPAR␥ agonists (11,12,41). However, it is not known if PPAR␥ is required for apoptosis induction of human B lymphocytes.…”

mentioning

confidence: 99%

The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms

Ray

Akbıyık

Phipps

2006

The Journal of Immunology

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Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARγ ligands, including the endogenous ligand 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARγ for apoptosis induction is unknown. In this study, we used a PPARγ dominant-negative approach and a small molecule irreversible PPARγ antagonist and found that these inhibitors prevented PPARγ activation but did not prevent B cell apoptosis induced by 15d-PGJ2 or ciglitazone. In addition, a PPARγ agonist that is a structural analog of 15d-PGJ2, and lacks the electrophilic carbon of the 15d-PGJ2 cyclopentenone ring, activated PPARγ but did not kill B lymphocytes, further supporting a non-PPARγ-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ2 and ciglitazone on reactive oxygen species were investigated. 15d-PGJ2, but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ2 structure in the apoptosis mechanism. In addition, 15d-PGJ2 caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ2, but not by ciglitazone. These findings indicate that the expression of PPARγ may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARγ agonists. Furthermore, these new findings support continued investigation into the use of PPARγ agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.

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“…This assumption is supported by data showing pronounced effects of PPAR␥ ligands as opposed to PPAR␣ agonists on proliferation and cytotoxicity both in human ECs (Figure 3) and in B lymphocytes and B lymphoma cells. 28 As a major control point of gene expression, transcriptional activation has been previously identified as a key regulatory mechanism of VEGFR2 expression. Our data indicate that the repressive effects of fibrates on VEGFR2 occur at the transcriptional level via activation of PPAR␣.…”

Section: Discussionmentioning

confidence: 99%

PPARα Activators Inhibit Vascular Endothelial Growth Factor Receptor-2 Expression by Repressing Sp1-Dependent DNA Binding and Transactivation

Meißner

Stein

Urbich

et al. 2004

Circulation Research

104

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Abstract-Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, originally implicated in the regulation of lipid and glucose homeostasis. In addition, natural and synthetic PPAR activators may control inflammatory processes by inhibition of distinct proinflammatory genes. As signaling via the vascular endothelial growth factor receptor-2 (VEGFR2) pathway is critical for angiogenic responses during chronic inflammation, we explored whether known antiinflammatory effects of PPAR ligands are mediated in part through diminished VEGFR2 expression. In this study, PPAR␣ agonists are found to inhibit endothelial VEGFR2 expression, whereas predominant PPAR␥ ligands remained without discernible effects.

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Human B Lymphocytes and B Lymphomas Express PPAR-γ and Are Killed by PPAR-γ Agonists

Cited by 121 publications

References 41 publications

Preclinical assessment of curcumin as a potential therapy for B‐CLL

Preclinical assessment of curcumin as a potential therapy for B‐CLL

The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms

PPARα Activators Inhibit Vascular Endothelial Growth Factor Receptor-2 Expression by Repressing Sp1-Dependent DNA Binding and Transactivation

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