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Search Results: 1 - 10 of 117 matches for " Hisataka Moriwaki "
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Synergistic Effects of PPAR Ligands and Retinoids in Cancer Treatment
Masahito Shimizu,Hisataka Moriwaki
PPAR Research , 2008, DOI: 10.1155/2008/181047
Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs), which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXR due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPAR/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXR was inhibited. We here in review the synergistic antitumor effects produced by the combination of the PPAR, especially PPAR, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXR because the inhibition of RXR phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.
Targeting Receptor Tyrosine Kinases for Chemoprevention by Green Tea Catechin, EGCG
Masahito Shimizu,Yohei Shirakami,Hisataka Moriwaki
International Journal of Molecular Sciences , 2008, DOI: 10.3390/ijms9061034
Abstract: Tea is one of the most popular beverages consumed worldwide. Epidemiologic studies show an inverse relationship between consumption of tea, especially green tea, and development of cancers. Numerous in vivo and in vitro studies indicate strong chemopreventive effects for green tea and its constituents against cancers of various organs. (–)-Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, appears to be the most biologically active constituent in tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells. Recent studies indicate that the receptor tyrosine kinases (RTKs) are one of the critical targets of EGCG to inhibit cancer cell growth. EGCG inhibits the activation of EGFR (erbB1), HER2 (neu/erbB2) and also HER3 (neu/erbB3), which belong to subclass I of the RTK superfamily, in various types of human cancer cells. The activation of IGF-1 and VEGF receptors, the other members of RTK family, is also inhibited by EGCG. In addition, EGCG alters membrane lipid organization and thus inhibits the dimerization and activation of EGFR. Therefore, EGCG inhibits the Ras/MAPK and PI3K/Akt signaling pathways, which are RTK-related cell signaling pathways, as well as the activation of AP-1 and NF-κB, thereby modulating the expression of target genes which are associated with induction of apoptosis and cell cycle arrest in cancer cells. These findings are significant because abnormalities in the expression and function of RTKs and their downstream effectors play a critical role in the development of several types of human malignancies. In this paper we review evidence indicating that EGCG exerts anticancer effects, at least in part, through inhibition of activation of the specific RTKs and conclude that targeting RTKs and related signaling pathway by tea catechins might be a promising strategy for the prevention of human cancers.
Cancer Chemoprevention by Carotenoids
Takuji Tanaka,Masahito Shnimizu,Hisataka Moriwaki
Molecules , 2012, DOI: 10.3390/molecules17033202
Abstract: Carotenoids are natural fat-soluble pigments that provide bright coloration to plants and animals. Dietary intake of carotenoids is inversely associated with the risk of a variety of cancers in different tissues. Preclinical studies have shown that some carotenoids have potent antitumor effects both in vitro and in vivo, suggesting potential preventive and/or therapeutic roles for the compounds. Since chemoprevention is one of the most important strategies in the control of cancer development, molecular mechanism-based cancer chemoprevention using carotenoids seems to be an attractive approach. Various carotenoids, such as β-carotene, a-carotene, lycopene, lutein, zeaxanthin, β-cryptoxanthin, fucoxanthin, canthaxanthin and astaxanthin, have been proven to have anti-carcinogenic activity in several tissues, although high doses of β-carotene failed to exhibit chemopreventive activity in clinical trials. In this review, cancer prevention using carotenoids are reviewed and the possible mechanisms of action are described.
Targeting Receptor Tyrosine Kinases for Chemoprevention by Green Tea Catechin, EGCG
Masahito Shimizu,Yohei Shirakami,Hisataka Moriwaki
International Journal of Molecular Sciences , 2008,
Abstract: Tea is one of the most popular beverages consumed worldwide. Epidemiologic studies show an inverse relationship between consumption of tea, especially green tea, and development of cancers. Numerous in vivo and in vitro studies indicate strong chemopreventive effects for green tea and its constituents against cancers of various organs. ( ¢ € “)-Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, appears to be the most biologically active constituent in tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells. Recent studies indicate that the receptor tyrosine kinases (RTKs) are one of the critical targets of EGCG to inhibit cancer cell growth. EGCG inhibits the activation of EGFR (erbB1), HER2 (neu/erbB2) and also HER3 (neu/erbB3), which belong to subclass I of the RTK superfamily, in various types of human cancer cells. The activation of IGF-1 and VEGF receptors, the other members of RTK family, is also inhibited by EGCG. In addition, EGCG alters membrane lipid organization and thus inhibits the dimerization and activation of EGFR. Therefore, EGCG inhibits the Ras/MAPK and PI3K/Akt signaling pathways, which are RTK-related cell signaling pathways, as well as the activation of AP-1 and NF- oB, thereby modulating the expression of target genes which are associated with induction of apoptosis and cell cycle arrest in cancer cells. These findings are significant because abnormalities in the expression and function of RTKs and their downstream effectors play a critical role in the development of several types of human malignancies. In this paper we review evidence indicating that EGCG exerts anticancer effects, at least in part, through inhibition of activation of the specific RTKs and conclude that targeting RTKs and related signaling pathway by tea catechins might be a promising strategy for the prevention of human cancers.
Rikkunshi-to Partially Reverses Cancer Chemotherapy-Induced Decrease in Plasma Valproic Acid Concentration in a Patient with Malignant Lymphoma  [PDF]
Masashi Ishihara, Kiyoyuki Kitaichi, Katsuhiko Matsuura, Hiroshi Nakamura, Hisashi Tsurumi, Hisataka Moriwaki, Yoshinori Itoh
Chinese Medicine (CM) , 2011, DOI: 10.4236/cm.2011.22011
Abstract: A fifty-five-year-old male patient with malignant lymphoma who took oral valproic acid (VPA) tablets and itraconazole (ITZ) capsles received 3 courses of cancer chemotherapy, including 2 courses of a combination of rituximab/methotrexate/ifosphamide/etoposide/ carboplatin/ methylpredonisolon (R-IMVP16/CBDCA regimen) and subsequent one course of a combination of rituximab/ranimustine/citara bine/etoposide/merphalan (R-MEAM regimen). Plasma concentration of VPA dramatically decreased below the therapeutic concentration after the first and second chemotherapy and seizures appeared in both cases. Plasma concentration of ITZ was also lowered after the second chemotherapy course. At the third chemotherapy, Rikkunshi-to, a Japanese herbal medicine, was prescribed for 14 days. Plasma VPA concentration decreased, though to a lesser extent, after chemotherapy, in which the level was near the border of therapeutic concentration. No convulsion was observed. Therefore, care should be taken to monitor plasma drug concentration during cancer chemotherapy. Rikkunshi-to may be useful to alleviate the chemotherapy-induced decrease in plasma concentrations of orally administered drugs.
Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis
Masahito Shimizu,Masaya Kubota,Takuji Tanaka,Hisataka Moriwaki
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms13010579
Abstract: Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.
C57BL/KsJ-db/db-ApcMin/+ Mice Exhibit an Increased Incidence of Intestinal Neoplasms
Kazuya Hata,Masaya Kubota,Masahito Shimizu,Hisataka Moriwaki,Toshiya Kuno,Takuji Tanaka,Akira Hara,Yoshinobu Hirose
International Journal of Molecular Sciences , 2011, DOI: 10.3390/ijms12118133
Abstract: The numbers of obese people and diabetic patients are ever increasing. Obesity and diabetes are high-risk conditions for chronic diseases, including certain types of cancer, such as colorectal cancer (CRC). The aim of this study was to develop a novel animal model in order to clarify the pathobiology of CRC development in obese and diabetic patients. We developed an animal model of obesity and colorectal cancer by breeding the C57BL/KsJ- db /db (db/db) mouse, an animal model of obesity and type II diabetes, and the C57BL/6J- ApcMin/+ (Min/+) mouse, a model of familial adenomatous polyposis. At 15 weeks of age, the N9 backcross generation of C57BL/KsJ- db /db- ApcMin/+ (db/db-Min/+) mice developed an increased incidence and multiplicity of adenomas in the intestinal tract when compared to the db/m-Min/+ and m/m-Min/+ mice. Blood biochemical profile showed significant increases in insulin (8.3-fold to 11.7-fold), cholesterol (1.2-fold to 1.7-fold), and triglyceride (1.2-fold to 1.3-fold) in the db/db-Min/+ mice, when compared to those of the db/m-Min/+ and m/m-Min/+ mice. Increases (1.4-fold to 2.6-fold) in RNA levels of insulin-like growth factor (IGF)-1, IRF-1R, and IGF-2 were also observed in the db/db-Min/+ mice. These results suggested that the IGFs, as well as hyperlipidemia and hyperinsulinemia, promoted adenoma formation in the db/db-Min/+ mice. Our results thus suggested that the db/db-Min/+ mice should be invaluable for studies on the pathogenesis of CRC in obese and diabetes patients and the therapy and prevention of CRC in these patients.
Dual induction of caspase 3- and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells
Hideki Tatsukawa, Tetsuro Sano, Yayoi Fukaya, Naoto Ishibashi, Makiko Watanabe, Masataka Okuno, Hisataka Moriwaki, Soichi Kojima
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-4
Abstract: Human hepatocellular carcinoma cells in culture, as well as nude mice transplanted with hepatocellular carcinoma cells and rats given with N-diethylnitrosamine were treated with acyclic retinoid. Changes in activated caspase 3 and transglutaminase 2 (TG2) levels, Sp1 cross-linking and its activities, expression of epidermal growth factor receptor, and apoptotic levels were measured.Acyclic retinoid simultaneously stimulated the activation of caspase 3, and the expression, nuclear localization and crosslinking activity of TG2, resulting in crosslinking and inactivation of the transcription factor, Sp1, thereby reducing expression of epidermal growth factor receptor and cell death in three hepatocellular carcinoma cell lines. These effects were partially restored by a caspase inhibitor, transfection of antisense TG2, restoration of functional Sp1, or an excess of epidermal growth factor. Nuclear expression of TG2 and crosslinked Sp1, as also activated caspase 3 were found in both hepatocellular carcinoma cells transplanted into nude mice and cancerous regions within the liver in N-diethylnitrosamine-induced hepatocarcinogenesis model in rats, following treatment of animals with acyclic retinoid.Treatment with acyclic retinoid produces a dual activation of caspase 3 and TG2 induced apoptosis of hepatocellular carcinoma cells via modification and inactivation of Sp1, resulting in reduced expression of epidermal growth factor receptor.Hepatocellular carcinoma (HCC) has high mortality rate because of it frequent rate of recurrence [1]. Acyclic retinoid (ACR), a synthetic retinoid, prevents the recurrence and development of HCC in patients after surgical removal of the primary tumors by inducing apoptosis in HCC cells [2,3]. Retinoid X receptor (RXR) α is highly phosphorylated and loses its activity as a transcriptional factor during carcinogenesis in HCC [4]. ACR prevents this aberrant hyper-phosphorylation of RXRα by suppressing the Ras-extracellular signal regulated kin
The Effect of Acyclic Retinoid on the Metabolomic Profiles of Hepatocytes and Hepatocellular Carcinoma Cells
Xian-Yang Qin, Feifei Wei, Masaru Tanokura, Naoto Ishibashi, Masahito Shimizu, Hisataka Moriwaki, Soichi Kojima
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082860
Abstract: Background/Purpose Acyclic retinoid (ACR) is a promising chemopreventive agent for hepatocellular carcinoma (HCC) that selectively inhibits the growth of HCC cells (JHH7) but not normal hepatic cells (Hc). To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR)-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses in JHH7 and Hc cells after treatment with ACR. Methodology/Principal Findings NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH) or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5′-triphosphate (ATP), the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells). Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4), a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively). Conclusions/Significance The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways identified in this study will be important targets of the anti-cancer activity of ACR.
Tumor Necrosis Factor-α Promotes Cholestasis-Induced Liver Fibrosis in the Mouse through Tissue Inhibitor of Metalloproteinase-1 Production in Hepatic Stellate Cells
Yosuke Osawa, Masato Hoshi, Ichiro Yasuda, Toshiji Saibara, Hisataka Moriwaki, Osamu Kozawa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065251
Abstract: Tumor necrosis factor (TNF)-α, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-α on hepatic stellate cell (HSC) activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-α in cholestasis-induced liver fibrosis was examined by comparing between TNF-α?/? mice and TNF-α+/+ mice after bile duct ligation (BDL). Serum TNF-α levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL). TNF-α deficiency reduced liver fibrosis without affecting liver injury, inflammatory cell infiltration, and liver regeneration after CBDL+CDL. Increased expression levels of collagen α1(I) mRNA, transforming growth factor (TGF)-β mRNA, and α-smooth muscle actin (αSMA) protein by CBDL+CDL in the livers of TNF-α?/? mice were comparable to those in TNF-α+/+ mice. Exogenous administration of TNF-α decreased collagen α1(I) mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-α?/? mice is regulated in post-transcriptional level. Tissue inhibitor of metalloproteinase (TIMP)-1 plays a crucial role in the pathogenesis of liver fibrosis. TIMP-1 expression in HSCs in the liver was increased by CBDL+CDL, and the induction was lower in TNF-α?/? mice than in TNF-α+/+ mice. Fibrosis in the lobe of TIMP-1?/? mice with partial BDL was also reduced. These findings indicate that TNF-α produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-α and TIMP-1 may become a new therapeutic strategy for treating liver fibrosis in cholestatic liver injury.
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