HUMULONE, A POTENT COX-2 INHIBITOR FROM BEER HOP, INHIBITS ANGIOGENESIS

• Project/Area Number: 16590445
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: THE TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE
• Principal Investigator: SHIMAMURA Mariko THE TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE, RESEARCHER, 東京都臨床医学総合研究所, 主任研究員 (00124462)
• Co-Investigator(Kenkyū-buntansha): TOBE Hiroyasu KOCHI NATIONAL COLLEGE OF TECHNOLOGY, DEPARTMENT OF MATERIALS SCIENCE AND TECHNOLOGY, PROFESSOR, 物質工学科, 教授 (30300643)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: HUMULONE / ANGIOGENESIS / CYCLOOXYGENASE-2 / ANGIOGENESIS INHIBITION / CAM / ENDOTHELIAL CELLS / TRANSCRIPTION INHIBITOR / METASTASIS / cyclooxygenase 2 / 鶏卵漿尿膜 / 抗腫瘍作用 / 腫瘍細胞 / cycloxygenase2 / dorsal air sac

Research Abstract

Angiogenesis, the formation of new capillary blood vessels for supplying oxygen and nutrients, is essential for their continuous growth and metastasis of solid tumors. The inhibition of tumor angiogenesis by potent angiogenic inhibitors may be a useful approach for cancer therapy. Recently, cyclooxygenase (COX), particularly COX-2, was postulated to be involved in tumor growth, metastasis and angiogenesis. To find a new potent angiogenic inhibitor, we focused our previous finding that humulone, a bitter acid from beer hop (Humulus lupulus L.) was a potent inhibitor of bone resorption and inhibited catalytic activity of cyclooxygenase-2 and more potently the transcription of COX-2 gene.
We first examined the effect of humulone on angiogenesis, using chick embryo chorioallantoic membranes (CAM) and vascular endothelial and tumor cells. Humulone significantly prevented in vivo angiogenesis in CAM in a dose dependent manner. Humulone potently inhibited the proliferation of endothelial cells stimulated by bFGF, VEGF and serum. It also suppressed in vitro angiogenesis of vascular endothelial tube formation and production of angiogenic factor (VEGF) in endothelial and tumor cells. We next examined the effects of the synthesized or purified compounds derived from humulone on angiogenesis in CAM. Among the compounds tested, humulone was the most potent angiogenesis inhibitor. Therefore, we synthesized large volume of humulone and examined in vivo assays in mice. Humulone inhibited tumor-induced angiogenesis in mouse dorsal air sac assay and also suppressed spontaneous lung metastasis of tumor cells by intraperitoneal administration. On the bases of these results, humulone is a potent angiogenesis inhibitor, and may be a novel powerful tool for the therapy in various angiogenic diseases involving solid tumor, rheumatoid arthritis and diabetic retinopathy.

Research Products

• [Journal Article] Cancer prevention and anti-metastatic effect by oral administration of bovine lactoferrin. (2005)
  • Author(s): Shimamura, M., et al.
  • Journal Title: Carcinogenesis and Modification of Carcinogenesis 1 Pages: 229-242
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Levels of spinorphin in carebrospinal fluid derived from patients with pain increase with decreasing dipeptidyl peptidase III. (2005)
  • Author(s): Shimamura, M., et al.
  • Journal Title: Pain Research 20 Pages: 27-34
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cancer prevention and anti-metastatic effect by oral administration of bovine lactoferrin. (2005)
  • Author(s): Iigo, M., Shimamura, M., Hirano, S., Nabeshima, K., Ohkubo, S., Tamura Y., Tsuda, H.
  • Journal Title: Carcinogenesis & Modification of Carcinogenesis Pages: 229-242
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Levels of spinorphin in cerebrospinal fluid derived from patients with pain increase with decreasing dipeptidyl peptidase III. (2005)
  • Author(s): Yamamoto, Y., Sato, H., Fukasaku, S., Hiramatsu, K., Tai, S., Shimamura M., Hazato, T.
  • Journal Title: Pain Research 20 Pages: 27-34
  • NAID: 10015444541
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Two-dimensional electrophoretic analysis of disease-associated proteins in human cerebrospinal fluid from patients with rheumatoid arthritis. (2005)
  • Author(s): Yamamoto, Y., Akita, Y., Tai, S., Fukasaku, S., Yamaguchi, T., Oshizawa, T., Yamaoka, K., Shimamura, M., Hazato, T.
  • Journal Title: J.Electrophoresis 49 Pages: 23-27
  • NAID: 10015570338
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antitumor effect of a novel IL6/IL12 family cytokine IL-27. (2005)
  • Author(s): Yoshimoto, T., Hisada, M., Shimizu, M., Shimamura, M., Mizuguchi, J.
  • Journal Title: Rinshomeneki 43 Pages: 123-128
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Levels of spinorphin in cerebrospinal fluid derived from patients with pain increase with decreasing dipeptidyl peptidase III. (2005)
  • Author(s): Shimamura, M., et al.
  • Journal Title: Pain Research 20 Pages: 27-34
  • NAID: 10015444541
• [Journal Article] Two-dimensional electrophoretic analysis of disease-associated proteins in human cerebrospinal fluid from patients with rheumatoid arthritis. (2005)
  • Author(s): Shimamura, M., et al.
  • Journal Title: J.Electrophoresis 49 Pages: 23-27
  • NAID: 10015570338
• [Journal Article] ウシラクトフェリン免疫能増強および血管新生阻害作用による発がん抑制と臨床応用. (2005)
  • Author(s): 島村眞里子, 他
  • Journal Title: Milk Science 54 Pages: 273-274
• [Journal Article] がん予防-多機能生理活性物質ラクトフェリンからメッセージ-. (2005)
  • Author(s): 島村眞里子, 他
  • Journal Title: Milk Science 53 Pages: 225-229
• [Journal Article] 新しいIL-6/IL-12ファミリーサイトカインIL-27の抗腫瘍効果 (2005)
  • Author(s): 島村眞里子, 他
  • Journal Title: 臨床免疫 43 Pages: 123-128
• [Journal Article] Levels of spinorphin in cerebrospinal fluid derived from patients with pain increase with decreasing dipeptidyl peptidase III (2005)
  • Author(s): Shimamura, N.et al.
  • Journal Title: Pain Research (In press)
  • NAID: 10015444541
• [Journal Article] Two-dimensional electrophoretic analysis of disease-associated proteins in human cerebrospinal fluid from patients with rheumatoid arthritis. (2005)
  • Author(s): Shimamura, N.et al.
  • Journal Title: J.Electrophoresis (In press)
  • NAID: 10015570338
• [Journal Article] Bovine lactoferrin inhibits tumor-induced angiogenesis. (2004)
  • Author(s): Shimamura, M., et al.
  • Journal Title: Intl. J. Cancer 111 Pages: 111-116
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Orlly administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa : A possible explanation for inhbition of carcinogenesis and metastasis. (2004)
  • Author(s): Shimamura, M., et al.
  • Journal Title: Cytokines 25 Pages: 36-44
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Angiogenesis inhibitor TX-1898 : syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers. (2004)
  • Author(s): Shimamura, M., et al.
  • Journal Title: Bioorg. Med. Chem. 12 Pages: 4917-4927
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Design of hypoxia targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione (2004)
  • Author(s): Shimamura, et al.
  • Journal Title: Biochim. Biophys. Acta-protein and proteomics- 1697 Pages: 29-38
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bovine lactoferrin inhibits tumor-induced angiogenesis. (2004)
  • Author(s): Shimamura, M., Yamamoto, Y., Ashino, H., Oikawa, T., Hazato, T., Tsuda, H., Iigo, M.
  • Journal Title: Int.J.Cancer 111 Pages: 111-116
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa : A possible explanation for inhibition of carcinogenesis and metastasis. (2004)
  • Author(s): Iigo, M., Shimamura, M., Matsuda, E., Fujita, K., Nomoto, H., Satoh, J., Kojima, K., Moore, M., Tsuda, H.
  • Journal Title: Cytokine 25 Pages: 36-44
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiogenesis inhibitor TX-1898 : syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitro imidazole hypoxic cell radiosensitizers. (2004)
  • Author(s): Jin CZ, Nagasawa H, Shimamura M, Uto Y, Inayama S, Takeuchi Y, Kirk KL, Hori H.
  • Journal Title: Bioorg Med Chem. 12 Pages: 4917-4927
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Design of hypoxia targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione. (2004)
  • Author(s): Hori, H., Nagasawa, H., Uto, Y., Ohkura, K., Kirk, K.L, Uehara, Y., Shimamura, M.
  • Journal Title: Biochim.Biophys.Acta -protein and proteomics-. 1697 Pages: 29-38
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cancer prevention by lactoferrin is accompanied by inhibition of angiogenesis. (2004)
  • Author(s): Iigo, M., Shimamura, M., Nabeshima, K., Wakabayashi, H., Ohkubo, S., Tamura, Y., Tsuda, H.
  • Journal Title: Milk Science 53 Pages: 273-274
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cancer prevention -A message from multifunctional natural compounds-. (2004)
  • Author(s): Tsuda, H., Ohshima, H., Fukamachi, K., Iigo, M., Takasuka, N., Matsuda, E., Sekine, K., ohkubo, S., Kohzu, T., Shimamura, M.
  • Journal Title: Milk Science 53 Pages: 225-229
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bovine lactoferrin inhibits tomor-induced angiogenesis (2004)
  • Author(s): Shimamura, M.et al.
  • Journal Title: Intl.J.Cancer 111 Pages: 111-116
• [Journal Article] Orally administered bovine lactoferrin induces caspase-1 and inter-leukin-18 in the mouse intestinal mucosa (2004)
  • Author(s): Shimamura, M.et al.
  • Journal Title: Cytokine 25 Pages: 36-44
• [Journal Article] Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcdarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers (2004)
  • Author(s): Shimamura, M.et al.
  • Journal Title: Bioorg Med Chem 12 Pages: 4917-4927
• [Journal Article] Design of hypoxia targeting protein tyrosine kinase inhibitor using an 2innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione (2004)
  • Author(s): Shimamura, M.et al.
  • Journal Title: Biochim.Biophys.Acta -protein and proteomics- 1697 Pages: 29-38
• [Book] がん予防食品開発の新展開・予防医学におけるバイオマーカーの評価システム (2005)
  • Author(s): 島村眞里子他
  • Publisher: ラクトフェリン・多機能性天然由来物質によるがん予防
  • Description: 「研究成果報告書概要(和文)」より
• [Book] がん予防食品開発の新展開 -予防医学におけるバイオマーカーの評価システム- (2005)
  • Author(s): 島村眞里子, 他
  • Publisher: シーエムシー出版