Peroxisome Proliferator Activator Receptor-γ Agonists and 15-Deoxy-Δ12,1412,14-PGJ2 Induce Apoptosis in Normal and Malignant B-Lineage Cells

Padilla, Josué; Kaur, Kuljeet; Cao, Hanwei; Smith, Terry J.; Phipps, Richard P.

doi:10.4049/jimmunol.165.12.6941

Cited by 146 publications

(118 citation statements)

References 37 publications

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“…Whereas activation of PPARg induces apoptosis (Elstner et al, 1998;Padilla et al, 2000), RB has been demonstrated to have an antiapoptotic function (Morgenbesser et al, 1994;Pan and Griep, 1995). This is consistent with our finding that in the absence of RB, PPARg-mediated apoptosis is enhanced.…”

Section: Pparg Rb and Apoptosissupporting

confidence: 82%

PPARγ controls cell proliferation and apoptosis in an RB-dependent manner

et al. 2003

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The nuclear receptor PPARc is implicated in the control of cell proliferation and apoptosis. However, the molecular mechanisms by which it controls these processes remain largely elusive. We show here that PPARc activation in the presence of the retinoblastoma protein (RB) results in the arrest of cells at the G1 phase of the cell cycle, whereas in the absence of RB, cells accumulate in G2/M, endoreduplicate, and undergo apoptosis. Through the use of HDAC inhibitors and coimmunoprecipitations, we furthermore demonstrate that the effects of RB on PPARc-mediated control of the cell cycle and apoptosis depend on the recruitment of histone deacetylase 3 (HDAC3) to PPARc. In combination, these data hence demonstrate that the effects of PPARc on cell proliferation and apoptosis are dependent on the presence of an RB-HDAC3 complex.

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Section: Pparg Rb and Apoptosissupporting

confidence: 82%

PPARγ controls cell proliferation and apoptosis in an RB-dependent manner

et al. 2003

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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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“…The role of B cells in modulating MS is becoming more appreciated. Interestingly, B cells express PPAR-γ and the PPAR-γ ligands 15d-PGJ 2 and thiazolidinediones inhibit Bcell proliferation and induce apoptosis of these cells [37,38]. PPAR-γ agonists can also potentiate the apoptosis of macrophages [23].…”

Section: Ppar-γ: Effects On Peripheral Leukocytesmentioning

confidence: 99%

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Drew

Storer

et al. 2005

Brain Research Reviews

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses.Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-α that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS.Previously, we and others demonstrated that PPAR-γ agonists including 15d-PGJ 2 are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-γ modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ 2 is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ 2 acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ 2 and 9-cis RA inhibit cell activation through the formation of PPAR-γ/ RXR heterodimers. Interestingly, PGA 2 , which like 15d-PGJ 2 is a cyclopentenone prostaglandin, but which unlike 15d-PGJ 2 does not bind PPAR-γ, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ 2 inhibits microglial cell activation by PPAR-γ-dependent as well as PPAR-γ-independent mechanisms. The studies further suggest that the PPAR-γ agonist 15d-PGJ 2 in combination with retinoids may be effective in the treatment of MS.

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Peroxisome Proliferator Activator Receptor-γ Agonists and 15-Deoxy-Δ12,1412,14-PGJ2 Induce Apoptosis in Normal and Malignant B-Lineage Cells

Cited by 146 publications

References 37 publications

PPARγ controls cell proliferation and apoptosis in an RB-dependent manner

PPARγ controls cell proliferation and apoptosis in an RB-dependent manner

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

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

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