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Tanaka T.,The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP | Tanaka T.,Gifu University
Journal of Experimental and Clinical Medicine(Taiwan) | Year: 2013

Cancer chemoprevention, which is defined as the use of natural or synthetic chemical agents to reverse or suppress carcinogenic processes, is an important strategy to reduce the risk of cancer. Many laboratory studies have suggested beneficial effects of various dietary compounds (phytochemicals) in reducing the risk of cancer. Apoptosis (programmed cell death) plays a critical role in normal physiological functions, but there is a dysregulation of apoptosis in cancer as well as in other chronic diseases, such as neurodegenerative disorders. Many natural cancer chemopreventive compounds are known to induce apoptosis. At the molecular level, dietary chemopreventive compounds can modulate a number of key elements of cell signal transduction pathways involved in the apoptotic process. This review stresses the importance of apoptosis induction by natural dietary agents for cancer chemoprevention. © 2013, Taipei Medical University. Published by Elsevier Taiwan LLC. Source


Tanaka T.,The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP | Hosokawa M.,Hokkaido University | Yasui Y.,Rakuno Gakuen University | Ishigamori R.,National Cancer Research Institute | Miyashita K.,Hokkaido University
International Journal of Molecular Sciences | Year: 2011

Conjugated fatty acids (CFA) have received increased interest because of their beneficial effects on human health, including preventing cancer development. Conjugated linoleic acids (CLA) are such CFA, and have been reviewed extensively for their multiple biological activities. In contrast to other types of CFAs including CLA that are found at low concentrations (less than 1%) in natural products, conjugated linolenic acids (CLN) are the only CFAs that occur in higher quantities in natural products. Some plant seeds contain a considerably high concentration of CLN (30 to 70 wt% lipid). Our research group has screened CLN from different plant seed oils to determine their cancer chemopreventive ability. This review describes the physiological functions of CLN isomers that occur in certain plant seeds. CLN are able to induce apoptosis through decrease of Bcl-2 protein in certain human cancer cell lines, increase expression of peroxisome proliferator-activated receptor (PPAR)-γ, and up-regulate gene expression of p53. Findings in our preclinical animal studies have indicated that feeding with CLN resulted in inhibition of colorectal tumorigenesis through modulation of apoptosis and expression of PPARγ and p53. In this review, we summarize chemopreventive efficacy of CLN against cancer development, especially colorectal cancer. © 2011 by the authors; licensee MDPI, Basel, Switzerland. Source


Terakura D.,Gifu University | Shimizu M.,Gifu University | Iwasa J.,Gifu University | Baba A.,Gifu University | And 9 more authors.
Carcinogenesis | Year: 2012

Obesity and its associated disorders, such as non-alcoholic steatohepatitis, increase the risk of hepatocellular carcinoma. Branched-chain amino acids (BCAA), which improve protein malnutrition in patients with liver cirrhosis, reduce the risk of hepatocellular carcinoma in these patients with obesity. In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ, p21CIP1 and p27KIP1 messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1β, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ and adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals. © The Author 2012. Published by Oxford University Press. All rights reserved. Source


Kuno T.,Gifu University | Hatano Y.,Gifu University | Tomita H.,Gifu University | Hara A.,Gifu University | And 7 more authors.
Carcinogenesis | Year: 2013

Magnesium (Mg) deficiency increases genomic instability and Mg intake has been reported to be inversely associated with a risk of colorectal cancer (CRC). This study was designed to determine whether organo-Mg in drinking water suppresses inflammation-associated colon carcinogenesis in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (AOM, 10mg/kg body weight) and followed by a 1week exposure to dextran sulfate sodium (DSS, 1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the drinking water containing 7, 35 or 175 p.p.m. organo-Mg for 13 weeks. The chemopreventive efficacy of organo-Mg was determined 16 weeks after the AOM exposure. Administration with organo-Mg at all doses caused a significant inhibition of CRC development (P< 0.01 and P< 0.001). Especially, the highest dose of organo-Mg significantly suppressed the occurrence of all the colonic pathological lesions (mucosal ulcer, dysplasia, adenoma and adenocarcinoma). Organo-Mg also significantly reduced the number of mitoses/anaphase bridging, as well as proliferation of CRC. Additionally, at week 4, organo-Mg lowered the messenger RNA expression of certain proinflammatory cytokines, such as interleukin-1β, interleukin-6, interferon-γ and inducible nitric oxide synthase in the lesion-free colorectal mucosa at week 4 but increased the Nrf-2 messenger RNA expression. Our findings that organo-Mg inhibits inflammation-related mouse colon carcinogenesis by modulating the proliferative activities and chromosomal instability of CRC and suppressing colonic inflammation may suggest potential use of organo-Mg for clinical chemoprevention trials of CRC in the inflamed colon. © The Author 2012. Published by Oxford University Press. All rights reserved. Source


Nakamura N.,Gifu University | Hara T.,Gifu University | Shimizu M.,Gifu University | Mabuchi R.,Gifu University | And 11 more authors.
International Journal of Hematology | Year: 2015

Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-d-tryptophan (d-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of d-1MT, mice were killed on day 28. Serum concentrations of l-kynurenine and l-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-γ, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. d-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum l-kynurenine/l-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-γ and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and d-1MT+CY groups. The number of Tregs in TDLNs in the d-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that d-1MT in combination with CY is an effective treatment for lymphoma in a mouse model. © 2015, The Japanese Society of Hematology. Source

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