Peroxisome proliferator-activated receptor γ ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats

Guo, Yantong; Leng, Xi-sheng; Li, Tao; Zhao, Jingming; Lin, Xiaoqin

doi:10.3748/wjg.v10.i23.3419

Cited by 14 publications

(13 citation statements)

References 21 publications

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“…PPARγ ligands can inhibit LPS-induced NO and TNFα production in cultured KCs and the inhibition was potentiated by co-treatment with RXR agonists [22]. However, it is not known whether PPARγ agonists have any role in reducing the effects of inflammation on NR genes in hepatocytes, although recent studies in humans with non-alcoholic steatohepatitis (NASH) support PPARγ ligands as potential anti-inflammatory agents [23,24].…”

Section: Introductionmentioning

confidence: 99%

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Ghose

Mulder

Furstenberg

et al. 2007

Journal of Hepatology

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Background/Aims-A recently-determined target of lipopolysaccharide (LPS) and cytokine signaling in liver is the central Type II nuclear receptor (NR) heterodimer partner, Retinoid X receptor α (RXRα). We sought to determine if rosiglitazone (Rosi) a peroxisome proliferator activated receptor γ(PPARγ) agonist with anti-inflammatory properties, can attenuate LPS and cytokineinduced molecular suppression of RXRα-regulated genes.Methods-In vivo, mice were gavage-fed Rosi for 3 days, prior to intraperitoneal injection of LPS, followed by harvest of liver and serum. In vitro, HepG2 cells were treated with IL-1β, ± short-term Rosi pretreatment. RNA was analyzed by quantitative RT-PCR, while nuclear and cytoplasmic proteins were analyzed by immunoblotting and gel shifts.Results-Rosi attenuated LPS-mediated suppression of RNA levels of several Type II NRregulated genes, including bile acid transporters and the major drug metabolizing enzyme, Cyp3a11, without affecting cytokine expression, suggesting a novel, direct anti-inflammatory effect in hepatocytes. Rosi suppressed the inflammation-induced nuclear export of RXRα, in both LPSinjected mice and IL-1β-treated HepG2 cells, leading to maintenance of nuclear RXRα levels and heterodimer binding activity.Conclusions-Rosi directly attenuates the suppressive effects of inflammation-induced cell signaling on nuclear RXRα levels in liver.

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Section: Introductionmentioning

confidence: 99%

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Ghose

Mulder

Furstenberg

et al. 2007

Journal of Hepatology

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“…24,25), breast cancer (26), colon cancer (27), and esophageal SCC (28). Accumulating data also show that PPARγ ligands suppress carcinogenesis in a wide range of rodent model systems, including colon (29), liver (30), tongue (25,31), breast (32), and lung (33) models.…”

Section: Introductionmentioning

confidence: 99%

Chemopreventive Effects of Pioglitazone on Chemically Induced Lung Carcinogenesis in Mice

Wang

James

Wang

et al. 2010

Molecular Cancer Therapeutics

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Pioglitazone [(RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione] is a ligand of nuclear receptor peroxisome proliferator-activated receptor γ that is approved for the treatment of type II diabetes mellitus. Activation of peroxisome proliferator-activated receptor γ has been associated with anticancer activities in a variety of cancer cell lines through inhibition of proliferation and promotion of apoptosis. We examined the effect of pioglitazone on lung cancer development in carcinogen-induced lung adenocarcinoma and squamous cell carcinoma (SCC). When pioglitazone was administered beginning 8 weeks after the first carcinogen treatment when microscopic adenomas already existed, pioglitazone significantly inhibited tumor load (sum of tumor volume per lung in average) by 64% (P < 0.05) in p53 wt/wt mice and 50% (P < 0.05) in p53 wt/Ala135Val mice in the lung adenocarcinoma model. Delayed administration of pioglitazone caused a limited (35%, P < 0.05) decrease in lung SCC. Induction of apoptosis occurred in both model systems. These data show that pioglitazone significantly inhibited progression of both adenocarcinoma and SCC in the two mouse model systems. Mol Cancer Ther; 9(11); 3074-82. ©2010 AACR.

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“…This is followed by the increase of the rate of transcription initiation of a large compendium of genes encoding proteins associated with lipid and glucose homeostasis [2]. Apart from established metabolic actions, PPARγ agonists exhibit antineoplastic effects through the inhibition of cell proliferation, induction of apoptosis, cell cycle arrest, terminal differentiation, and suppression of tumor angiogenesis and invasion [3,4], which was confirmed by several in vivo studies using animal models [5][6][7]. Recently, several studies have reported that PPARγ agonists monotherapy or a combination treatment with other chemotherapeutic drugs or molecular targets was beneficial for patients with different kinds of cancers, suggesting their application as antineoplastic agents [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 81%

Pyrimidinyl-arylpropionic acid derivatives: viable resources in the development of new antineoplastic agents

Xiong

Wang

et al. 2009

Invest New Drugs

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Numerous studies have documented that various naturally derived ligands or synthetic non-thiazolidinediones (TZD) as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown moderate or potent antitumor activities, which is PPARgamma independent or partially dependent. However, the PPARgamma agonistic or glucose-lowering activity is ranked first more often than antitumor activity to determine promising novel PPARgamma agonists for potential clinical use. In this study, we hypothesized that there might exist some compounds with less PPARgamma agonistic activity but potent antitumor activity. Thereafter, we evaluated the PPARgamma agonistic and antitumor activity of a novel series of alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives synthesized with the initial aim of developing novel PPARgamma agonists as hypoglycemic agents. MTT assay results revealed that several compounds were able to inhibit cell proliferation in a dose-dependent manner with IC(50) 12.7-29.7 microM, better than that of rosiglitazone (45.9-141 microM), although the PPARgamma agonistic activity of most compounds is much lower than rosiglitazone. Some compounds induced cell cycle arrest and apoptosis tested by Flow Cytometry. Oral administration of DH9 (100 mg/kg/d) for 21 days to BALB/c nude mice bearing xenografts including MGC-803, NCI-H460, HT-29 and OS-RC-2 cells significantly retarded tumor growth. DG8 and DJ5 showed benefits in some of the above four xenografts. Our findings demonstrate that these compounds have potent antitumor activity in vitro and in vivo and pyrimidinyl-arylpropionic acid derivatives might be viable resources in the development of new antineoplastic agents.

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Peroxisome proliferator-activated receptor γ ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats

Cited by 14 publications

References 21 publications

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Chemopreventive Effects of Pioglitazone on Chemically Induced Lung Carcinogenesis in Mice

Pyrimidinyl-arylpropionic acid derivatives: viable resources in the development of new antineoplastic agents

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