Combination chemoprevention of hepatocellular carcinoma with acyclic retinoid by targeting RXRαphosphorylation

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590838
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: MORIWAKI Hisataka 岐阜大学, 医学系研究科, 教授 (50174470)
• Co-Investigator(Kenkyū-buntansha): SHIMIZU Masahito 岐阜大学, 医学部附属病院, 助教 (90402198)
• Project Period (FY): 2009 – 2011
• Keywords: 非環式レチノイド / 核内受容体異常 / 併用化学発癌予防 / 肝細胞癌

Research Abstract

Acyclic retinoid, a synthetic retinoid targeting RXR., prevented the recurrence of hepatocellular carcinoma(HCC) in hepatitis C virus-positive patients in a phase II/III clinical trial. This agent also inhibits obesity-related liver tumorigenesis and acts synergistically with valproic acid, GW4064, a FXR ligand, and branched-chain amino acids in suppressing growth in human HCC cells, indicating that "combination chemoprevention" with acyclic retinoid as the key drug has great potential to become an effective strategy for the prevention of liver carcinogenesis.

Research Products

• [Journal Article] Combination of acyclic retinoid with branched-chain amino acids inhibits xenograft growth of human hepatoma cells in nude mice (2012)
  • Author(s): Shimizu M, Shirakami Y, Sakai H, Iwasa J, Shiraki M, Takai K, Naiki T, Moriwaki H
  • Journal Title: Hepatol Res Volume: (in press)
• [Journal Article] Synergistic growth inhibition of human hepatocellular carcinoma cells by acyclic retinoid and GW4064, a farnesoid X receptor ligand (2012)
  • Author(s): Ohno T, Shirakami Y, Shimizu M, Kubota M, Sakai H, Yasuda Y, Kochi T, Tsurumi H, Moriwaki H
  • Journal Title: Cancer Lett Volume: (in press)
• [Journal Article] Cancer chemoprevention by carotenoids (2012)
  • Author(s): Tanaka T, Shimizu M, Moriwaki H
  • Journal Title: Molecules Volume: 14, 17(3) Pages: 3202-3242
• [Journal Article] Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis (2012)
  • Author(s): Shimizu M, Kubota M, Tanaka T, Moriwaki H
  • Journal Title: Int J Mol Sci Volume: 13 Pages: 579-595
• [Journal Article] Suppression of azoxymethane-induced colonic preneoplastic lesions in rats by 1-methyltryptophan, an inhibitor of indoleamine 2, 3-dioxygenase (2012)
  • Author(s): Ogawa K, Hara T, Shimizu M, Ninomiya S, Nagano J, Sakai H, Hoshi M, Ito H, Tsurumi H, Saito K, Seishima M, Tanaka T, Moriwaki H
  • Journal Title: Cancer Sci Volume: 103 Pages: 951-958
  • DOI: doi:10.1111/j.1349-7006.2012.02237.x
• [Journal Article] Monosodium glutamate-induced diabetic mice are susceptible to azoxymethane-induced colon tumorigenesis (2012)
  • Author(s): Hata K, Kubota M, Shimizu M, Moriwaki H, Kuno T, Tanaka T, Hara A, Hirose Y
  • Journal Title: Carcinogenesis Volume: 33 Pages: 702-707
• [Journal Article] Preventive effects of curcumin on the development of azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db obese mice (2012)
  • Author(s): Kubota M, Shimizu M, Sakai H, Yasuda Y, Terakura D, Baba A, Ohno T, Tsurumi H, Tanaka T, Moriwaki H
  • Journal Title: Nutr Cancer Volume: 64 Pages: 72-79
• [Journal Article] Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BLKS/J-+(db)/+Lepr(db) mice (2011)
  • Author(s): Shimizu M, Sakai H, Shirakami Y, Iwasa J, Yasuda Y, Kubota M, Takai K, Tsurumi H, Tanaka T, Moriwaki H
  • Journal Title: Cancer Prev Res Volume: 4 Pages: 128-136
• [Journal Article] Preventive effects of(-)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db Mice (2011)
  • Author(s): Shimizu M, Sakai H, Shirakami Y, Yasuda Y, Kubota M, Terakura D, Baba A, Ohno T, Hara Y, Tanaka T, Moriwaki H
  • Journal Title: Cancer Prev Res Volume: 4 Pages: 396-403
• [Journal Article] Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice (2011)
  • Author(s): Shimizu M, Yasuda Y, Sakai H, Kubota M, Terakura D, Baba A, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H
  • Journal Title: BMC Cancer Volume: 11 Pages: 281
• [Journal Article] Cancer chemoprevention with green tea catechins by targeting receptor tyrosine kinases (2011)
  • Author(s): Shimizu M, Adachi S, Masuda M, Kozawa O, Moriwaki H
  • Journal Title: Mol Nutr Food Res Volume: 55 Pages: 832-843
• [Journal Article] Chemoprevention of hepatocellular carcinoma by acyclic retinoid (2011)
  • Author(s): Shimizu M, Sakai H, Moriwaki H
  • Journal Title: Front Biosci Volume: 16 Pages: 759-769
• [Journal Article] Rho-kinase inhibitor upregulates migration by altering focal adhesion formation via the Akt pathway in colon cancer cells (2011)
  • Author(s): Adachi S, Yasuda I, Nakashima M, Yamauchi T, Yoshioka T, Okano Y, Moriwaki H, Kozawa O
  • Journal Title: Eur J Pharmacol Volume: 650 Pages: 145-150
• [Journal Article] Ultraviolet irradiation can induce evasion of colon cancer cells from stimulation of epidermal growth factor (2011)
  • Author(s): Adachi S, Yasuda I, Nakashima M, Yamauchi T, Kawaguchi J, Shimizu M, Itani M, Nakamura M, Nishii Y, Yoshioka T, Hirose Y, Okano Y, Moriwaki H, Kozawa O
  • Journal Title: J Biol Chem Volume: 286 Pages: 26178-26187
• [Journal Article] Ultraviolet enhances the sensitivity of pancreatic cancer cells to gemcitabine by activation of 5' AMP-activated protein kinase (2011)
  • Author(s): Adachi S, Yasuda I, Kawaguchi J, Yamauchi T, Nakashima M, Itani M, Nakamura M, Yoshioka T, Moriwaki H, Kozawa O
  • Journal Title: Biochem Biophys Res Commun Volume: 414 Pages: 53-59
• [Journal Article] L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin (2011)
  • Author(s): Osawa Y, Kanamori H, Seki E, Hoshi M, Ohtani H, Yasuda Y, Ito H, Suetsugu A, Nagaki M, Moriwaki H, Saito K, Seishima M
  • Journal Title: J Biol Chem Volume: 286 Pages: 34800-34808
• [Journal Article] Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression (2011)
  • Author(s): Osawa Y, Seki E, Kodama Y, Suetsugu A, Miura K, Adachi M, Ito H, Shiratori Y, Banno Y, Olefsky JM, Nagaki M, Moriwaki H, Brenner DA, Seishima M
  • Journal Title: FASEB J Volume: 25 Pages: 1133-1144
• [Journal Article] Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2 (2011)
  • Author(s): Kitagawa J, Hara T, Tsurumi H, Ninomiya S, Ogawa K, Adachi S, Kanemura N, Kasahara S, Shimizu M, Moriwaki H
  • Journal Title: J Cancer Res Clin Oncol Volume: 137(5) Pages: 779-787
• [Journal Article] Renin-angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice (2011)
  • Author(s): Kubota M, Shimizu M, Sakai H, Yasuda Y, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H
  • Journal Title: Biochem Biophys Res Commun Volume: 410 Pages: 108-113
• [Journal Article] Inhibition of Rho-associated coiled-coil containing protein kinase enhances the activation of epidermal growth factor receptor in pancreatic cancer cells (2011)
  • Author(s): Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kawaguchi J, Hanamatsu T, Yoshioka T, Okano Y, Hirose Y, Kozawa O, Moriwaki H
  • Journal Title: Mol Cancer Volume: 10 Pages: 79
• [Journal Article] Phosphorylation status of heat shock protein 27 plays a key role in gemcitabine-induced apoptosis of pancreatic cancer cells (2011)
  • Author(s): Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kawaguchi J, Itani M, Yoshioka T, Matsushima-Nishiwaki R, Hirose Y, Kozawa O, Moriwaki H
  • Journal Title: Cancer Lett Volume: 313 Pages: 218-225
• [Journal Article] Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment (2011)
  • Author(s): Watanabe N, Takai K, Imai K, Shimizu M, Naiki T, Nagaki M, Moriwaki H
  • Journal Title: J Clin Biochem Nutr Volume: 49(3) Pages: 153-158
• [Journal Article] Possible role of visfatin in hepatoma progression and the effects of branched-chain amino acids on visfatin-induced proliferation in human hepatoma cells (2011)
  • Author(s): Ninomiya S, Shimizu M, Imai K, Takai K, Shiraki M, Hara T, Tsurumi H, Ishizaki S, Moriwaki H
  • Journal Title: Cancer Prev Res(Phila) Volume: 4(12) Pages: 2092-2100
• [Journal Article] C57BL/KsJ-db/db-Apc Mice Exhibit an Increased Incidence of Intestinal Neoplasms (2011)
  • Author(s): Hata K, Kubota M, Shimizu M, Moriwaki H, Kuno T, Tanaka T, Hara A, Hirose Y
  • Journal Title: Int J Mol Sci Volume: 12(11) Pages: 8133-8145
• [Journal Article] Dual induction of caspase 3-and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells (2011)
  • Author(s): Tatsukawa H, Sano T, Fukaya Y, Ishibashi N, Watanabe M, Okuno M, Moriwaki H, Kojima S
  • Journal Title: Mol Cancer Volume: 10 Pages: 4
• [Journal Article] Indirect calorimetry and anthropometry to estimate energy metabolism in patients with liver cirrhosis (2011)
  • Author(s): Terakura Y, Shiraki M, Nishimura K, Iwasa J, Nagaki M, Moriwaki H
  • Journal Title: J Nutr Sci Vitaminol Volume: 56 Pages: 372-379
• [Journal Article] Accumulation of refractory factors for pegylated interferon plus ribavirin therapy in older female patients with chronic hepatitis C (2010)
  • Author(s): Chayama K, Hayes CN, Yoshioka K, Moriwaki H, Okanoue T, Sakisaka S, Takehara T, Oketani M, Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H, Seike M, Ueno Y, Yotsuyanagi H, Kumada H
  • Journal Title: Hepatol Res Volume: 40 Pages: 1155-1167
• [Journal Article] Hepatic encephalopathy as a complication of liver cirrhosis : an Asian perspective (2010)
  • Author(s): Moriwaki H, Shiraki M, Iwasa J, Terakura Y
  • Journal Title: J Gastroenterol Hepatol Volume: 25 Pages: 858-863
• [Journal Article] Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model (2010)
  • Author(s): Ito H, Hoshi M, Ohtaki H, Taguchi A, Ando K, Ishikawa T, Osawa Y, Hara A, Moriwaki H, Saito K, Seishima M
  • Journal Title: J Immunol Volume: 185 Pages: 4554-4560
• [Journal Article] Role of acid sphingomyelinase of Kupffer cells in cholestatic liver injury in mice (2010)
  • Author(s): Osawa Y, Seki E, Adachi M, Suetsugu A, Ito H, Moriwaki H, Seishima M, Nagaki M
  • Journal Title: Hepatology Volume: 51 Pages: 237-245
• [Journal Article] Elevated serum tumor necrosis factor-alpha and soluble tumor necrosis factor receptors correlate with aberrant energy metabolism in liver cirrhosis (2010)
  • Author(s): Shiraki M, Terakura Y, Iwasa J, Shimizu M, Miwa Y, Murakami N, Nagaki M, Moriwaki H
  • Journal Title: Nutrition Volume: 26 Pages: 269-275
• [Journal Article] Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice (2010)
  • Author(s): Iwasa J, Shimizu M, Shiraki M, Shirakami Y, Sakai H, Terakura Y, Takai K, Tsurumi H, Tanaka T, Moriwaki H
  • Journal Title: Cancer Sci Volume: 101 Pages: 460-467
• [Journal Article] Insulin resistance raises the risk for recurrence of stage I hepatocellularcarcinoma after curative radiofrequency ablation in HCV-positive patiens : A prospective, case-series study (2010)
  • Author(s): Imai K, Takai K, Nishigaki Y, Shimizu S, Naiki T, Hayashi H, Uematsu T, Sugihara J, Tomita E, Shimizu M, Nagaki M, Moriwaki H
  • Journal Title: Hepatol Res Volume: 40 Pages: 376-382
• [Journal Article] The Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis, Ministry of Health, Labor and Welfare of Japan. Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan (2010)
  • Author(s): Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi N, Tanaka E, Chayama K, Sakisaka S, Takehara T, Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka K, Seike M, Yotsuyanagi H, Ueno Y
  • Journal Title: Hepatol Res Volume: 40 Pages: 1-7
• [Journal Article] The Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis, Ministry of Health, Labour and Welfare of Japan. Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan (2010)
  • Author(s): Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi N, Tanaka E, Chayama K, Sakisaka S, Takehara T, Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka K, Seike M, Yotsuyanagi H, Ueno Y
  • Journal Title: Hepatol Res Volume: 40 Pages: 8-13
• [Journal Article] Acyclic retinoid inhibits angiogenesis by suppressing the MAPK pathway (2010)
  • Author(s): Komi Y, Sogabe Y, Ishibashi N, Sato Y, Moriwaki H, Shimokado K, Kojima S
  • Journal Title: Lab Invest Volume: 90 Pages: 52-60
• [Journal Article] Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells (2009)
  • Author(s): Tatebe H, Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Tsurumi H, Moriwaki H
  • Journal Title: Cancer Lett Volume: 285 Pages: 210-217
• [Journal Article] Synergistic effects of acyclic retinoid and gemcitabine on growth inhibition in pancreatic cancer cells (2009)
  • Author(s): Nakagawa T, Shimizu M, Shirakami Y, Tatebe H, Yasuda I, Tsurumi H, Moriwaki H
  • Journal Title: Cancer Lett Volume: 273 Pages: 250-256
• [Journal Article] Strategy and mechanism for the prevention of hepatocellular carcinoma : phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention (2009)
  • Author(s): Shimizu M, Takai K, Moriwaki H
  • Journal Title: Cancer Sci Volume: 100 Pages: 369-374
• [Presentation] ワークショップ18「消化器疾患におけるprobioticsと機能性食品の有用性」緑茶カテキンを用いた肥満関連大腸および肝発癌予防 (2011)
  • Author(s): 清水雅仁、久保田全哉、森脇久隆
  • Organizer: JDDW 2011(第53回日本消化器病学会大会)
  • Place of Presentation: 福岡
  • Year and Date: 20111020-23
• [Presentation] シンポジウム「がん予防戦略の最前線」肥満関連分子異常を標的とした肝発癌化学予防 (2011)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: がん予防大会2011京都
  • Place of Presentation: 京都
  • Year and Date: 20110620-21
• [Presentation] ワークショップ7「Steatohepatitisの病態.その多様性と相同性.」非環式レチノイドによる肥満関連肝腫瘍形成の抑制 (2011)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: 第97回日本消化器病学会総会
  • Place of Presentation: 新潟
  • Year and Date: 20110513-15
• [Presentation] ワークショップ5「肝発癌・進展とインスリン抵抗性」インスリン抵抗性とIGF/IGF-1受容体シグナルを標的とした肥満関連肝発癌予防 (2010)
  • Author(s): 清水雅仁、岩砂淳平、森脇久隆
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: 山形
  • Year and Date: 20100527-28
• [Presentation] シンポジウム2「消化器癌と栄養療法」分枝鎖アミノ酸製剤(BCAA)を用いた肥満関連肝および大腸発癌の予防 (2010)
  • Author(s): 清水雅仁、白木亮、森脇久隆
  • Organizer: 第96回日本消化器病学会総会
  • Place of Presentation: 新潟
  • Year and Date: 20100422-24
• [Presentation] パネルディスカッション14「肝細胞癌の集学的治療の現状と近未来的治療(分子標的治療を含めて)」RXRαを標的分子とする非環式レチノイドを用いた併用肝発癌化学予防 (2009)
  • Author(s): 清水雅仁、久保田全哉、森脇久隆
  • Organizer: JDDW2009
  • Place of Presentation: 京都
  • Year and Date: 20091014-17
• [Presentation] ワークショップ23-1「Cancer prevention/chemoprevention」Supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver carcinogenesis in obese mice (2009)
  • Author(s): Shimizu M, Iwasa J, Tanaka T, Moriwaki H
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-03
• [Presentation] ワークショップ3「大腸癌の予防」緑茶カテキンによる大腸発癌予防-基礎および臨床的予備実験- (2009)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: 第95回日本消化器病学会総会
  • Place of Presentation: 札幌
  • Year and Date: 20090507-09
• [Presentation] ワークショップ4「肝細胞癌の予防」核内受容体RXRαを分子標的とする非環式レチノイドをkey drugとした併用肝発癌化学予防 (2009)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: 第95回日本消化器病学会総会
  • Place of Presentation: 札幌
  • Year and Date: 20090507-09
• [Presentation] シンポジウム5「メタボリック症候群と消化器癌」分枝鎖アミノ酸製剤(BCAA)による肥満関連肝発癌の抑制 (2009)
  • Author(s): 岩砂淳平、清水雅仁、森脇久隆
  • Organizer: 第95回日本消化器病学会総会
  • Place of Presentation: 札幌
  • Year and Date: 20090507-09