Troglitazone, a Ligand for Peroxisome Proliferator‐activated Receptor γ Inhibits Chemically‐induced Aberrant Crypt Foci in Rats

Kohno, Hiroyuki; Yoshitani, Shinichiro; Takashima, Shigeki; Okumura, Atsuko; Hosokawa, Masashi; Yamaguchi, Nobuo; Tanaka, Takuji

doi:10.1111/j.1349-7006.2001.tb01108.x

Cited by 49 publications

(34 citation statements)

References 47 publications

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“…In our study, dietary feeding of BMO enhanced PPAR␥ expression in nonlesional colonic mucosa. These results are of interest, since we recently demonstrated that synthetic ligands for PPAR␣ and PPAR␥ effectively inhibit AOMinduced ACF in rats, 26,43 and the findings were confirmed by Osawa et al 27 Thus, it may be possible that feedings with BMO suppresses colon carcinogenesis via altering PPAR␥ expression in colonic mucosa.…”

Section: Discussionsupporting

confidence: 57%

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Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane‐induced rat colon carcinogenesis through elevation of colonic PPARγ expression and alteration of lipid composition

Kohno

Yasui

Suzuki

et al. 2004

Intl Journal of Cancer

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Our previous short-term experiment demonstrated that seed oil from bitter melon (Momordica charantia) (BMO), which is rich in cis(c)9, trans(t)11, t13-conjugated linolenic acid (CLN), inhibited the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). In our study, the possible inhibitory effect of dietary administration of BMO on the development of colonic neoplasms was investigated using an animal colon carcinogenesis model initiated with a colon carcinogen AOM. Male F344 rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks to induce colon neoplasms. They also received diets containing 0.01%, 0.1% or 1% BMO for 32 weeks, starting 1 week before the first dosing of AOM. At the termination of the study (32 weeks), AOM induced 83% incidence (15/18 rats) of colonic adenocarcinoma. Dietary supplementation with 0.01% and 0.1% BMO caused significant reduction in the incidence (47% inhibition by 0.01% BMO, p<0.02; 40% inhibition by 0.1% BMO, p<0.05; and 17% inhibition by 1% BMO) and the multiplicity (64% inhibition by 0.01% BMO, p<0.005; 58% inhibition by 0.1% BMO, p<0.02; and 48% inhibition by 1% BMO, p<0.05) of colonic adenocarcinoma, though a clear dose response was not observed. Such inhibition was associated with the increased content of CLA (c9,t11-18:2) in the lipid composition in colonic mucosa and liver. Also, BMO administration in diet enhanced expression of peroxisome proliferator-activated receptor (PPAR) ␥ protein in the nonlesional colonic mucosa. These findings suggest that BMO rich in CLN can suppress AOM-induced colon carcinogenesis and the inhibition might be caused, in part, by modification of lipid composition in the colon and liver and/or increased expression of PPAR␥ protein level in the colon mucosa.

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Section: Discussionsupporting

confidence: 57%

“…Also, the expression of peroxisome proliferator-activated receptor (PPAR) ␥ in colonic mucosa and the lipid composition in the liver and colon were estimated to understand the possible mechanisms of modulatory effect of BMO in colon carcinogenesis since fatty acids might be an agonist for PPARs, 24 which suppress colon tumorigenesis. [25][26][27] …”

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confidence: 99%

Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane‐induced rat colon carcinogenesis through elevation of colonic PPARγ expression and alteration of lipid composition

Kohno

Yasui

Suzuki

et al. 2004

Intl Journal of Cancer

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“…32,33) We have shown that synthetic ligands for PPARγ prevent the development of carcinogen-induced preneoplastic ACF in the colon of rats. 34,35) Our recent investigation has confirmed these findings: a synthetic C E-mail: h-kohno@kanazawa-med.ac.jp PPARγ ligand effectively inhibits AOM-induced colon carcinogenesis in rats (Hirose, Y., et al, manuscript in preparation).…”

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confidence: 69%

Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically induced colon carcinogenesis in rats

et al. 2004

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Pomegranate (Punica granatum L.) seed oil (PGO) contains more than 70% cis(c)9,trans(t)11,c13-18:3 as conjugated linolenic acids (CLN). Our previous short-term experiment demonstrated that seed oil from bitter melon (Momordica charantia) (BMO), which is rich in c9,t11,t13-CLN, inhibited the occurrence of colonic aberrant crypt foci (ACF) induced by azoxymethane (AOM). In this study, we investigated the effect of dietary PGO on the development of AOM-induced colonic malignancies and compared it with that of conjugated linoleic acid (CLA). To induce colonic tumors, 6-week old male F344 rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks. One week before the AOM treatment they were started on diet containing 0.01%, 0.1%, or 1% PGO or 1% CLA for 32 weeks. Upon termination of the bioassay (32 weeks) colon tumors were evaluated histopathologically. AOM exposure produced colonic adenocarcinoma with an incidence of 81% and multiplicity of 1.88 ± ± ± ±1.54 at week 32. Administration of PGO in the diet significantly inhibited the incidence (AOM + + + +0.01% PGO, 44%, P < < < <0.05; AOM + + + +0.1% PGO, 38%, P < < < <0.01; AOM + + + +1% PGO, 56%) and the multiplicity (AOM + + + +0.01% PGO, 0.56 ± ± ± ±0.73, P < < < <0.01; AOM + + + +0.1% PGO, 0.50 ± ± ± ±0.73, P < < < <0.005; AOM + + + +1% PGO, 0.88 ± ± ± ±0.96, P < < < <0.05) of colonic adenocarcinomas, although a clear dose-response relationship was not observed at these dose levels. CLA feeding also slightly, but not significantly, reduced the incidence and multiplicity of colonic adenocarcinomas. The inhibition of colonic tumors by PGO was associated with an increased content of CLA (c9,t11-18:2) in the lipid fraction of colonic mucosa and liver. Also, administration of PGO in the diet elevated expression of peroxisome proliferator-activated receptor ( olon cancer is one of the leading causes of cancer deaths in Western countries. Globally, more than 875,000 men and women were afflicted with this cancer in 1996 and more than 510,000 died in the same year.

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“…[30][31][32] PPARg, a multifunctional nuclear receptor, induced alteration of protein production of EGFR and BAX in LA-treated IEC6 cells. Chen and Xu 33 reported that activation of PPARg decreases expression of EGFR and cyclin D1.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment

Sasaki

Yoshida

Sasaki

et al. 2005

Intl Journal of Cancer

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The effect of linoleic acid (LA) on growth and transformation of IEC6 intestinal cells was examined. IEC6 cells expressed mRNAs of 15-lipooxygenase (LOX15) and peroxisome proliferator-activated receptor (PPAR)c but not COX-2. Cell growth was suppressed by LA in a dose-dependent manner in IEC6 cells. Threeweek treatment with LA provided IEC6 cells a quiescent state. LA-induced growth inhibition was abrogated by exposure to antisense S-oligodeoxynucleotides (S-ODNs) for LOX15 and/or PPARc. In an in vitro carcinogenesis model, IEC6 cells, which had confirmed CYP2E1 expression and activity, were continuously treated with AOM and/or LA for 40 weeks. DNA injury in AOMtreated cells was suppressed to the control level by concurrent LA treatment. Colony formation of AOM-treated cells in soft agar was suppressed by treatment with LA, which was reversed by exposure to antisense S-ODNs for LOX15 and/or PPARc. AOMtreated IEC6 cells formed s.c. tumors in 9 of 12 mice, whereas AOM1LA-treated cells formed no tumor. IEC6 cells showed no remarkable alteration of protein production by AOM treatment, whereas cells treated with AOM1LA showed decreased epidermal growth factor receptor (EGFR) and phospho-EGFR and increased BAX. These findings suggest that LA inhibited AOMinduced transformation of COX-2-negative IEC6 cells, which was possibly mediated with PPARc ligands generated by LOX15 from LA. ' 2005 Wiley-Liss, Inc.Key words: linoleic acid; azoxymethane; colon cancer; transformation; peroxisome proliferator-activated receptor Colorectal cancer is the third most common malignant neoplasm worldwide and the third leading cause of cancer deaths in Japan. 1 The frequency of colon cancer in Japan is continuously increased along with the alteration of lifestyle from traditional Japanese to Western. In particular, the increase of fat intake and decrease of fiber intake have been regarded as the most important nutritional influence on colorectal cancer development. 2,3 Prostaglandins are bioactive lipids derived from the metabolites of membrane PUFAs and play important roles in a number of biologic processes. 4 COX-2-dependent overproduction of PGE 2 is hypothesized to be an important part of sustained proliferative and chronic inflammatory conditions. 5,6 Several in vivo studies hypothesize that a high amount of x-6 PUFA, such as LA, might enhance colorectal carcinogenesis via stimulation of colonic epithelial cell proliferation. 7-10 Indeed, rats treated with AOM and fed a diet supplemented with LA developed more tumors than animals treated with AOM alone. 11 AOM is a potent carcinogen, which induces colorectal cancers at high incidence in rats and mice. Adduct formation (mainly O 6 -methylguanine) by AOM induces point mutations in multiple genes such as K-ras and b-catenin. 12 In the present study, we used AOM as a carcinogen in the in vitro carcinogenesis model.The oxidative metabolites of LA, particularly 9-HODE, 13-HODE and 13-OXO, have biologic effects as PPARg ligands. 13 CLA, a strong ligand for PPARg, has a substantial anticarcin...

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Troglitazone, a Ligand for Peroxisome Proliferator‐activated Receptor γ Inhibits Chemically‐induced Aberrant Crypt Foci in Rats

Cited by 49 publications

References 47 publications

Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane‐induced rat colon carcinogenesis through elevation of colonic PPARγ expression and alteration of lipid composition

Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane‐induced rat colon carcinogenesis through elevation of colonic PPARγ expression and alteration of lipid composition

Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically induced colon carcinogenesis in rats

Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment

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