GW9662, a potent antagonist of PPARγ, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARγ agonist rosiglitazone, independently of PPARγ activation

Seargent, Jill M.; Yates, Elisabeth; Gill, Jason H.

doi:10.1038/sj.bjp.0705973

Cited by 172 publications

(140 citation statements)

References 14 publications

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“…Despite the fact that GW9662 fully reversed cannabidiol's inhibitory effect on A549 xenograft growth, the substance caused a pronounced tumor-regressive action when administered alone. Similar ambiguous findings have been reported in vitro where the PPAR-g agonist rosiglitazone and the PPAR-g antagonist GW9662 inhibited the growth of breast cancer cells to similar extents (36). In fact, PPAR-g antagonists have been shown to confer PPARg-independent antiproliferative, antiadhesive, and antimetastatic actions (for review see ref.…”

Section: Discussionsupporting

confidence: 71%

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

Ramer

Heinemann

Merkord

et al. 2013

Molecular Cancer Therapeutics

175

150

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The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-g in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-g antagonist), and siRNA targeting COX-2 and PPAR-g. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-g mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-g mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD 2 and 15-deoxy-D 12,14 -PGJ 2 (15d-PGJ 2 ) caused a translocation of PPAR-g to the nucleus and induced a PPAR-g-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-g in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-g and a subsequent nuclear translocation of PPAR-g by COX-2-dependent PGs. Mol Cancer Ther; 12(1); 69-82. Ó2012 AACR.

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Section: Discussionsupporting

confidence: 71%

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

Ramer

Heinemann

Merkord

et al. 2013

Molecular Cancer Therapeutics

175

150

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“…mine if the effects of probiotics on the epithelial barrier and cytokine secretion were dependent on PPAR␥ activation, a group of mice were treated with a selective PPAR␥ antagonist, GW9662, 30 minutes before LPS/GalN injection. 28 As shown in Fig. 8, the inhibition of PPAR␥ abrogated the ability of probiotics to protect against an LPS/GalN-induced breakdown in colonic barrier function and cytokine secretion.…”

Section: Resultsmentioning

confidence: 75%

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

et al. 2007

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A breakdown in intestinal barrier function and increased bacterial translocation are key events in the pathogenesis of sepsis and liver disease. Altering gut microflora with noninvasive and immunomodulatory probiotic organisms has been proposed as an adjunctive therapy to reduce the level of bacterial translocation and prevent the onset of sepsis. The purpose of this study was to determine the efficacy of a probiotic compound in attenuating hepatic and intestinal injury in a mouse model of sepsis. Wild-type and interleukin-10 (IL-10) gene-deficient 129 Sv/Ev mice were fed the probiotic compound VSL#3 for 7 days. To induce sepsis, the mice were injected with lipopolysaccharide (LPS) and D-galactosamine (GalN) in the presence and absence of the peroxisome proliferator-activated receptor gamma (PPAR␥) inhibitor GW9662. The mice were killed after 6 hours, and their colons were removed for the measurement of the cytokine production and epithelial function. The functional permeability was assessed by the mannitol movement and cyclic adenosine monophosphate-dependent chloride secretion in tissue mounted in Ussing chambers. The livers were analyzed for bacterial translocation, cytokine production, histological injury, and PPAR␥ levels. The tissue levels of tumor necrosis factor alpha, interferon gamma, IL-6, and IL-12p35 ribonucleic acid were measured by semiquantitative reverse transcription polymerase chain reaction. L iver dysfunction and failure contribute to the high mortality rates seen in patients with Gram-negative sepsis. The presence of lipopolysaccharide (LPS) from Gram-negative bacteria in the systemic circulation results in the activation of the innate immune system and the secretion of high levels of proinflammatory cytokines. In animal models, LPS challenge can induce a systemic reaction resulting in a sepsis-like condition characterized by fever, hypotension, and widespread tissue damage. D-Galactosamine (GalN) increases the susceptibility of mice to LPS-induced shock by impairing liver metabolism. 1 Challenging mice with low doses of LPS in conjunction with GalN results in massive liver apoptosis and increased mortality.Tumor necrosis factor alpha (TNF-␣) plays a central role in the overwhelming systemic inflammatory response to LPS. 2 However, the complete blockade of TNF-␣ production does not improve survival in animals or humans 3 The activation of nuclear factor kappa B (NF-B) has been shown to play a key role in the pathogenesis of sepsis and is a pivotal step in the regulation of several immune and proinflammatory genes, including TNF-␣. 4 The modulation of NF-B activity has been proposed as a strategy for reducing the mortality associated with sepsis. Peroxisome proliferator-activated receptor gamma (PPAR␥) is a nuclear hormone receptor and transcription

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“…One possibility for the requirement of very high doses to inhibit cell viability is that the endogenous PPARg receptors, which are often overexpressed in cancer, may need to be saturated prior to intracellular levels of TZD rising sufficiently to mediate anti-tumour effects. Indeed, Seargent et al (2004) demonstrated that the PPARg antagonist GW9662 selectively occupied PPARg receptors, yet enhanced rosiglitazone's anti-tumour effects in breast cancer cells, supporting the concept that by binding to PPARg, GW9662 permitted a higher intracellular level of rosiglitazone (Seargent et al 2004). Alternatively, the amount of TZD that can enter a tumour cell may be limited.…”

Section: Discussionmentioning

confidence: 91%

Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-α, CH11 and CYC202

Mody

Dharker²,

Bloomston³

et al. 2007

Endocr Relat Cancer

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Peroxisome proliferator-activated receptor-g (PPARg) is a member of the nuclear hormone superfamily and has multiple endogenous and pharmacological ligands, including 15-deoxy-D 12,14 -prostaglandin J 2 and two thiazolidinediones (TZD), rosiglitazone and pioglitazone, which are used clinically to treat type-2 diabetes mellitus. PPARg agonists regulate development, cellular growth and metabolism in various tissues and have been documented to decrease cellular proliferation and to induce apoptosis of various tumour phenotypes, including breast cancer. However, the full spectrum of anti-tumour effects occurs only at suprapharmacological doses. In this study, we investigated the mechanism of rosiglitazone-induced anti-tumour effects of MDA-MB-231 human breast cancer cells, and used that information to predict rosiglitazone-induced sensitization of breast cancer cells to the effects of other compounds. We first confirmed that 100 mM rosiglitazone, but not lower doses, decreases MDA-MB-231 cell viability in vitro. We then used microarray gene expression analysis to determine early rosiglitazone-induced gene expression changes after 4-h exposure, which included 1298 genes that we grouped into functional categories. We selectively confirmed rosiglitazonemediated effects on expression of key regulators of breast cancer proliferation and apoptosis, including p53, p21 and Bax. Finally, we used this information to predict that rosiglitazone would sensitize MDA-MB-231 cells to the anti-tumour effects of CH11, which trimerizes Fas, as well as tumour necrosis factor-a. Moreover, we used the confirmed array data to predict cooperative activity of rosiglitazone and R-roscovitine (CYC202), an inhibitor of multiple cyclin-dependent kinases. We conclude that microarray analysis can determine early TZD-modulated changes in gene expression that help to predict effective in vitro drug combinations.

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GW9662, a potent antagonist of PPARγ, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARγ agonist rosiglitazone, independently of PPARγ activation

Cited by 172 publications

References 14 publications

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-α, CH11 and CYC202

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