Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-<i>db/db</i> Mice

Shimizu, Masahito; Sakai, Hidetaka; Shirakami, Yohei; Yasuda, Yoshitaka; Kubota, Minoru; Terakura, Daishi; Baba, Atsushi; Ohno, Tomohiro; Hara, Yukihiko; Tanaka, Takuji; Moriwaki, Hisataka

doi:10.1158/1940-6207.capr-10-0331

Cited by 77 publications

(73 citation statements)

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“…significantly associated with the development of liver tumors in obese mice, and that inhibiting the activation of these signaling pathways is critical to the prevention of obesity-related liver tumorigenesis (34,35). These reports (34,35), together with the present findings that specific inhibitors of PI3K, MEK1, and GSK-3b significantly suppress visfatin-induced proliferation in HCC cells, suggest that visfatin and its related signaling pathways might be effective targets for inhibiting obesity-related liver carcinogenesis.…”

Section: Discussionsupporting

confidence: 62%

“…These reports (34,35), together with the present findings that specific inhibitors of PI3K, MEK1, and GSK-3b significantly suppress visfatin-induced proliferation in HCC cells, suggest that visfatin and its related signaling pathways might be effective targets for inhibiting obesity-related liver carcinogenesis.…”

Section: Discussionsupporting

confidence: 61%

“…These findings are significant when considering the possibility of BCAA as a chemopreventive agent for HCCs because GSK-3b phosphorylation is closely associated with liver carcinogenesis (41). Phosphorylation of GSK-3b is also involved in the development of liver tumors in obese mice, and inhibition of this kinase effectively suppresses obesityrelated liver tumorigenesis (35). Conversely, a recent study has shown that visfatin exerts antiapoptotic effects in HCC cells, and this might be associated with the enzymatic synthesis of NAD þ (15).…”

Section: Discussionmentioning

confidence: 96%

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Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Ninomiya

Shimizu

Imai

et al. 2011

Cancer Prevention Research

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Obesity and related metabolic abnormalities, including adipocytokine dysbalance, are risk factors for hepatocellular carcinoma (HCC). Visfatin, an adipocytokine that is highly expressed in visceral fat, is suggested to play a role in the progression of human malignancies. Branched-chain amino acids (BCAA) reduce the incidence of HCC in obese patients with liver cirrhosis and prevent obesity-related liver carcinogenesis in mice. In this study, we investigated the possible role of visfatin on HCC progression and the effects of BCAA on visfatin-induced proliferation of HCC cells. In patients with HCCs, serum visfatin levels were significantly correlated with stage progression and tumor enlargement. Visfatin preferentially stimulated the proliferation of HepG2, Hep3B, and HuH7 human HCC cells compared with Hc normal hepatocytes. Visfatin phosphorylated extracellular signal-regulated kinase (ERK), Akt, and GSK-3b proteins in HepG2 cells. LY294002 [a phosphoinositide-3-kinase (PI3K) inhibitor], PD98059 [a MAP/ERK 1 kinase (MEK1) inhibitor], CHIR99021 (a GSK-3b inhibitor), and BCAA significantly inhibited visfatin-induced proliferation in HepG2 cells. BCAA also inhibited phosphorylation of GSK-3b, increased cellular levels of p21 CIP1 , caused cell-cycle arrest in G 0 /G 1 phase, and induced apoptosis in HCC cells in the presence of visfatin. These findings suggest that visfatin plays a critical role in the proliferation of HCC cells and may be associated with the progression of this malignancy. In addition, BCAA might inhibit obesity-related liver carcinogenesis by targeting and, possibly, by overcoming the stimulatory effects of visfatin.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 96%

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Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Ninomiya

Shimizu

Imai

et al. 2011

Cancer Prevention Research

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“…In addition, HCC development is frequently associated with chronic inflammation and subsequent liver cirrhosis induced by a persistent infection with hepatitis viruses. Recent evidence also indicates that obesity and related metabolic abnormalities, especially insulin resistance, increase the risk for live cancer [105,106], while GTCs appear to exert anti-obesity and anti-diabetic activity [107,108]. Therefore, well-designed interventional clinical trials should be conducted to investigate whether GTCs are able to prevent the development of HCC in high-risk patients with viral liver cirrhosis and obesity.…”

Section: Clinical Interventional Studiesmentioning

confidence: 99%

Dietary Phytochemicals as Cancer Preventive Agents: Efficacy and Mechanisms

Sakai¹

2015

J Bioanal Biomed

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Despite significant advances in cancer therapeutic modalities, available anti-tumor drugs display limited efficacy and sometimes carry a risk of severe adverse side effect. Therefore, it is important to identify and develop cancer chemopreventive agents without toxicity. Epidemiological examinations in human populations and experimental rodent studies provide evidence that certain types of phytochemicals suppress development and growth of cancers at various organ sites. A number of clinical investigations have been also conducted and shown that dietary phytochemicals are able to inhibit tumorigenesis, indicating several phytochemicals are regarded as cancer chemopreventive agents. Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, is considered as the most biologically active constituent in drinking tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells. EGCG appears to directly target receptor tyrosine kinases with inhibiting activation of the receptors and down-stream signaling pathways. In addition, EGCG has improving effects against obesity and insulin resistance, which leads to suppressing the development of obesity-related malignancies. Other polyphenolic phytochemicals, including curcumin and resveratrol, are also reported to exert anti-cancer effect. In this review article, we summarize the potential of dietary phytochemicals as anti-cancer drugs and those possible mechanisms against cancer, especially chemopreventive effect of green tea catechins.

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“…In previous studies, various pathophysiological mechanisms linking obesity to cancer have been suggested. Insulin resistance and subsequent abnormal activation of insulin-like growth factor (IGF) and the IGF-1 axis has been considered to play a key role in carcinogenesis (van Kruijsdijk et al, 2009;Shimizu et al, 2011). Other possible mechanisms include dysfunction of adipose tissue due to dysregulation of adipocytokines such as adiponectin, leptin, and plasminogen activator inhibitor-1 resulting from the enlargement of adipocytes (Shimizu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

No Effect of High Fat Diet-Induced Obesity on Spontaneous Reporter Gene Mutations in gpt Delta Mice

Takasu

Ishii²,

Matsushita³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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A large number of epidemiological studies have demonstrated that obesity is a risk factor for several human cancers. Several animal studies using rodents with diet-induced or genetic obesity have also demonstrated that obesity can promote tumor development. However, the effects of obesity on the early stages of carcinogenesis, and especially on the spontaneous occurrence of somatic gene mutations, remain unclear. To investigate the effects of obesity on the rate of spontaneous gene mutations, we performed reporter gene mutation assays in liver, kidney, and colon, organs in which obesity appears to be associated with cancer development on the basis of epidemiological or animal studies, in mice with high fat diet (HFD)-induced obesity. Six-week-old male and female C57BL/6 gpt delta mice were fed HFD or standard diet (STD) for 13 or 26 weeks. At the end of the experiments, reporter gene mutation assays of liver, kidney, and colon were performed. Final body weights and serum leptin levels of male and female mice fed HFD for 13 or 26 weeks were significantly increased compared with corresponding STD-fed groups. Reporter gene mutation assays of liver, kidney, and colon revealed that there were no significant differences in gpt or Spi -mutant frequencies between STD-and HFD-fed mice in either the 13-week or 26-week groups. These results indicate that HFD treatment and consequent obesity does not appear to influence the spontaneous occurrence of somatic gene mutations.

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Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

Cited by 77 publications

References 50 publications

Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Dietary Phytochemicals as Cancer Preventive Agents: Efficacy and Mechanisms

No Effect of High Fat Diet-Induced Obesity on Spontaneous Reporter Gene Mutations in gpt Delta Mice

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