Disease relevance of Lopac-M-6191

• LPA-mediated proliferation was blocked by VPC-32179, a competitive antagonist of LPA(1) and LPA(3) receptors, and by pertussis toxin, and it was also attenuated by GW9662, a selective antagonist of peroxisome proliferator-activated receptor (PPAR)-gamma [1].
• METHODS: Rats were pretreated with LPS (1 mg/kg, IP, 24 hours prior to ischemia) in the absence (control) or presence of the selective PPARgamma antagonist GW9662 (1 mg/kg, IP, 24 and 12 hours prior to ischemia) [2].
• Treatment of HF diet-fed mice with GW9662 revealed that this compound prevented HF diet-induced obesity without affecting food intake [3].
• The effects of AS-6 on TNF-alpha-stimulated VCAM-1 and CX3CL1 expression were abolished in cells transfected with an adenovirus expressing dominant-negative PPARgamma and in cells treated with a PPARgamma specific inhibitor, GW9662, confirming again that the anti-inflammatory effect of AS-6 was PPARgamma-dependent [4].
• PPARgamma expression is a feature of esophageal cancer cell lines, and in the present investigation, the PPARgamma antagonists T0070907 and GW9662 could induce loss of invasion but could not induce growth reduction or apoptosis at low concentrations (< 10 mM) [5].

High impact information on Lopac-M-6191

• Neointima-inducing LPA analogs up-regulated the CD36 scavenger receptor in vitro and in vivo and elicited dedifferentiation of cultured vascular smooth muscle cells that was prevented by GW9662 [6].
• Interestingly, this inhibitory effect can be mimicked by both natural as well as synthetic peroxisome proliferator-activated receptor gamma1 (PPARgamma1) ligands and can be blocked by the irreversible PPARgamma antagonist GW 9662 [7].
• In KU7 cells, induction of caveolin-1 by each of the PPARgamma agonists was significantly down-regulated after cotreatment with the PPARgamma antagonist GW9662 [8].
• Furthermore, the capacity of all of these treatments to potentiate HL-60 cell differentiation was significantly reduced in the presence of the PPARgamma-antagonist GW 9662 [9].
• A PPARgamma antagonist, GW9662, did not block this effect, although a PTP inhibitor abrogated it [10].

Biological context of Lopac-M-6191

• Addition of geranylgeranyl pyrophosphate ammonium salt or GW9662 markedly inhibited the anthocyanin-induced increase of ABCA1 gene expression and apoAI-mediated cholesterol efflux [11].
• Next, both PPARgamma and p53 were involved in the cleavage of caspases-9 and DNA fragmentation induced by BRL, given that GW9662 and an expression vector for p53 antisense blunted these effects [12].
• The PPAR-gamma-specific ligand rosiglitazone induced PPAR response element (PPRE)-mediated activity in a concentration-dependent manner, whereas the PPAR-gamma-specific irreversible inhibitor GW9662 fully inhibited this induction [13].
• This effect was attenuated by a PPAR-gamma inhibitor [2-chloro-5-nitro-N-phenyl-benzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-gamma ligand rosiglitazone [14].
• Low doses (0.1-1 microM) of PPARgamma inhibitors (T0070907, GW9662 and BADGE) did not affect cell survival, while higher doses (10-100 microM) of all 3 PPARgamma inhibitors caused caspase-dependent apoptosis in HT-29, Caco-2 and LoVo CRC cell lines [15].

Anatomical context of Lopac-M-6191

• Unexpectedly, GW9662, a PPARgamma antagonist, increases lymphocyte IFN-gamma expression [16].
• Although CDDO and CDDO-Im both bind and transactivate peroxisome proliferator-activated receptor (PPAR) gamma, the irreversible PPARgamma antagonist GW9662 does not block the ability of either CDDO or CDDO-Im to induce differentiation; moreover, PPARgamma-null fibroblasts are still sensitive to the growth-suppressive effects of CDDO [17].
• The functional activity of GW9662 as an antagonist of PPARgamma was confirmed in an assay of adipocyte differentiation [18].
• Antagonizing PPARgamma activity by GW9662 or BADGE potently blocked Ang II-induced neurite outgrowth (Ang II + GW9662: 6.6 +/- 1.5-fold, p < 0.05; Ang II + BADGE: 1.3 +/- 0.7-fold, p < 0.01) [19].
• GW9662 suppressed any increase in the amount of visceral adipose tissue, but it did not change HF diet-induced glucose intolerance [3].

Associations of Lopac-M-6191 with other chemical compounds

• Troglitazone, a selective peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, enhanced COX-2 expression, while GW9662, a specific PPARgamma antagonist, relieved the suppressive effect of 15d-PGJ(2) [20].
• Extracellular TGF-beta1 levels were rapidly increased after treatment with pioglitazone in a peroxisome proliferator-activated receptor (PPAR)-gamma-dependent mechanism because this secretion was blocked by the PPAR-gamma inhibitor GW9662 [21].
• Stimulation of the Ipf1 promoter by rosiglitazone was unaffected by the presence of the peroxisome proliferator activated receptor gamma antagonist GW9662 [22].
• Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662 [18].
• The ability of PPARgamma agonists and TBH to induce COX-2 expression and PGE(2) production was blocked by pretreatment with the specific PPARgamma antagonist GW9662 [23].

Gene context of Lopac-M-6191

• These drugs also activated peroxisome proliferator-activated receptor gamma (PPARgamma) at concentration ranges that increase TFF2 expression, and upregulated TFF2 expression was suppressed by GW9662, a specific inhibitor of PPARgamma [24].
• The PPARgamma antagonist GW9662 was shown to block completely PPARgamma-ligand induction of CD36 gene expression, but had little effect on the action of RA [25].
• There was no effect of 15d-PGJ(2) or troglitazone on PPAR-gamma protein, and GW9662 failed to alleviate 15d-PGJ(2) and troglitazone inhibition of IL-6 and TNF-alpha release in placenta, amnion and choriodecidua [26].
• The selective PPARgamma ligand rosiglitazone increased PTEN expression in AsPC-1 cells; concurrent treatment with GW9662, which inhibits PPARgamma activation, prevented the increase in PTEN protein levels [27].
• To confirm the involvement of PPARgamma in thiazolidinedione-induced CXCR4 down-regulation, we used PPARgamma antagonists GW9662 and T0070907, both of which completely blocked the effect of rosiglitazone on CXCR4 expression [28].

Analytical, diagnostic and therapeutic context of Lopac-M-6191

• The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture experiments, suggests that this compound may be a useful tool for elucidation of the role of PPARgamma in biological processes [18].
• The selective PPAR-gamma antagonist GW9662 (2-chloro-5-nitrobenzanilide) was used in rat models of 1) regional myocardial I/R, 2) ischemic preconditioning, and 3) delayed cardioprotection by endotoxin [29].
• Western blot results indicated that both pioglitazone and resveratrol markedly inhibited the NF-kappaB pathway through suppressing IkappaB protein phosphorylation in macrophages, although this effect of resveratrol was not reversed by GW9662 [30].

References