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分子標的医薬探索寄附講座

多くの疾患機構が,細胞内シグナル伝達の異常で説明できるようになりました。そして異常なシグナル分子を選んで,その活性を抑制して治療効果を示す「分子標的医薬」が注目されています。分子標的医薬は疾患の原因をピンポイントで攻撃するので,活性が選択的で,副作用が小さい特徴があります。さらに低分子化合物を用いることで,今までと同じように治療ができるので,すぐ使える治療法になります。本講座(平成24〜28年度)は製薬企業や医療法人の支援を受け,私たちは疾患に有効な低分子シグナル伝達阻害剤を探索し,新しい化学療法剤の開発基礎研究,及び阻害剤を用いた病態解析の研究を行っています。

教育方針

生物学は記憶する学問ではなく,理論的で1をきいて10を知ることができる学問分野になりました。また,基本的な化学は生物学や医学の理解や研究にとても役に立ちます。そこで,私たちの研究を知っていただくこと,さらに研究に参加していただくことで,そのような新しい生物学を紹介したいと思っています。

活動・研究内容

私たちの見出したNF-kappa B阻害剤DHMEQは選択性の高い阻害剤で,動物実験で毒性を示さず,強力な抗炎症・抗癌活性を示しました。本講座ではDHMEQの開発基礎研究を行い,さらに微生物や植物の産生する生理活性物質から新しいシグナル伝達阻害物質を探索して副作用の少ない新規薬剤の創製を目指しています。最近,さらに進化したNF-kappa B阻害剤や組織の線維化を阻害する天然物を見出しました。新しいNF-kappa B阻害剤の有用性を見出すこと,DHMEQを用いて疾患の機構を解明すること,及び抗線維化医薬を開発する研究をしています。また,多くの国内外の大学や研究所と共同研究をしています。私たちの研究内容を広く知っていただくように多くの学会発表と論文発表を行いたいと思っています。

スタッフ紹介

氏名 職名 専門分野
梅澤 一夫 教授 生化学
クルラウィー・シリポング 大学院生 細胞生物学
宇梶 珠未 大学院生 細胞生物学
リン・インチ 大学院生 細胞生物学

研究テーマ

氏名 研究テーマ
梅澤 一夫
  • シグナル伝達阻害剤の天然からの探索と分子デザイン
  • シグナル伝達阻害剤を用いた疾患の機構解析
  • 新しい機構で働く抗炎症・抗癌剤の開発
クルラウィー・シリポング
  • NF-kappa β 阻害剤の探索と抗炎症活性の評価
宇梶 珠未
  • がん転移阻害物質の探索と作用機構の解析
リン・インチ
  • 細胞浸潤阻害物質の探索と作用機構の解析

分子標的医薬探索研究とDHMEQの発見

左上:探索研究のプロセス
右上:細胞内シグナル伝達と今までに見つけた阻害剤の標的分子
左下:NF-kappa B阻害剤DHMEQの発見
右下:NF-kappa B活性化のシグナル伝達とDHMEQの阻害機構

DHMEQの作用機構・疾患抑制と抗線維化活性のある植物由来コノフィリン

左上:DHMEQによるNF-kappa B構成因子への結合と活性阻害
右上:DHMEQによる多くのin vivo疾患モデルの抑制
左下:「腹腔内細胞のNF-kappa Bを阻害すると多くの難治性疾患が改善する」提案
右下:植物由来コノフィリンは膵ベータ細胞を増やし,膵島線維化を抑制する

研究室からのお知らせ

DHMEQを用いた多くの研究成果から,炎症や癌における腹腔内細胞の重要性を提唱しています。近未来にNF-kappa B阻害剤DHMEQを腹腔内投与して多くの難治性炎症疾患,癌を改善できると考えています。研究室(研究棟211)にはお気軽にお立ち寄り下さい。

2012年以降の刊行論文

1. E. Ota, M. Takeiri, M. Tachibana, Y. Ishikawa, K. Umezawa and S. Nishiyama: Synthesis and biological evaluation of molecular probes based on the 9-methylstreptimidone derivative DTCM-glutarimide. Bioorganic & Medicinal Chemistry Letters 22: 164-167, 2012.

2. T. Fukushima, M. Kawaguchi, K. Yorita, H. Tanaka, K. Umezawa and H. Kataoka: Antitumor effect of dehydroxymethylepoxyquinomicin (DHMEQ), a small molecule inhibitor of nuclear factor-kappa B, on glioblastoma. Neuro-Oncology 14: 19-28, 2012.

3. H. Hosoi, N. Kawai, H. Hagiwara, T. Suzuki, A. Nakazaki, K. Takao, K. Umezawa and S. Kobayashi: Determination of the absolute structure of (+)-akaterpin. Chem. Pharm. Bull. 60: 137-143, 2012

4. R. Saito, S. Yamada, Y. Yamamoto, T. Kodera, A. Hara, Y. Tanaka, F. Kimura, I.

Takei, K. Umezawa and I. Kojima: Conophylline suppresses pancreatic stellate cells and improves islet fibrosis in Goto-Kakizaki rats. Endocrinology 153: 621-630, 2012.

5. M. Takeiri, K. Horie, D. Takahashi, M. Watanabe, R. Horie, S. Simizu and K. Umezawa: Involvement of DNA binding domain in the cellular stability and importin affinity of NF-kappa B component RelB. Org. Biomol. Chem. 10: 3053-3059, 2012.

6. T. Funakoshi, K. Yamashita, N. Ichikawa, M. Fukai, T. Suzuki, R. Goto, T. Oura, N. Kobayashi, T. Katsurada, S. Ichihara, M. Ozaki, K. Umezawa, and Satoru Todo: A novel NF- kappa B inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice. Journal of Crohn’s and Colotis 6: 215-225, 2012.

7. T. Yasukagawa, Y. Niwa, S. Simizu and K. Umezawa: Suppression of cellular invasion by glybenclamide through inhibited secretion of platelet-derived growth factor in ovarian clear cell carcinoma ES-2 cells. FEBS Lett. :1504–1509, 2012.

8. N. Noma, S. Simizu, Y. Kambayashi, Y. Kabe, M. Suematsu, and K. Umezawa: Involvement of NF-kappa B-mediated expression of galectin-3-binding protein in tumor necrosis factor-alpha-induced breast cancer cell adhesion. Oncology Reports 27: 2080-2084, 2012.

9. Y. Niwa, C. Matsui, N. Sukumwang, H. Iinuma, Y. Ikeda, T. Koyano, T. Kovitayakorn, S. Simizu and K. Umezawa: Inhibition of lysenin-induced hemolysis by all-E-lutein derived from the plant Dalbergia latifolia. Planta Medica 78: 957-961, 2012.

10. M. Kawata, D. Koinuma, T. Ogami, K. Umezawa, C. Iwata, T. Watabe and K. Miyazono: TGF-beta-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by proinflammatory cytokines derived from RAW 264.7 macrophage cells. J. Biochem. 151: 205-216, 2012.

11. R. Goto, K. Yamashita, T. Aoyagi, S. Ueki, M. Uno, T. Oura, N. Kobayashi, R. Igarashi, S. Shibasaki, K. Wakayama, G. Hirokata, T. Shibata, K. Umezawa, M. Ozaki, and S. Todo: The immunomodulatory effect of nuclear factor-kappa B inhibition by dehydroxymethylepoxyquinomicin in combination with donor-specific blood transfusion. Transplantation 93: 777-786, 2012.

12. N. Lampiasi, A. Azzolina1, K Umezawa, G. Montalto, J. A. McCubrey and M. Cervello: The novel NF-kappa B inhibitor DHMEQ synergizes with Celecoxib to exert antitumor effects on human liver cancer cells by a ROS-dependent mechanism. Cancer Lett. 322: 35-44, 2012.

13. K. Hinohara, S. Kobayashi, S. Simizu, K. Tada, E. Tsuji, K. Nishioka, K. Umezawa, M. Mori, H. Kanauchi, T. Ogawa, J. Inoue, A. T and N. Gotoh: ErbB/NFkappaB signaling controls self-renewal of breast cancer stem cells. Proc. Natl. Acad. Sci. USA 109: 6584-6589, 2012.

14. K. Shimizu, S. Konno, M. Ozaki, K. Umezawa, K. Yamashita, S. Todo and M. Nishimura: Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma. Clinical & Experimental Allergy 42: 1273–1281.

15. A. Kaneda, Sh. Kh. Gantsev, and K. Umezawa: Inhibition of cellular invasion and induction of anoikis in mouse melanoma cells by an anti-inflammatory agent DTCM-glutarimide. Creative Surgery and Oncology 2012: 4-9, 2012.

16. M. Takeiri, E. Ota, S. Nishiyama, H. Kiyota, S. Simizu and K. Umezawa: Structure-activity relationship of 9-methylstreptimidone that induces selective apoptosis in adult T-cell leukemia cells. Oncology Res. 20: 7-14, 2012.

17. M. S. Brassesco, J. A. Pezuk, A. G. Morales, J. C. de Oliveira, E. T. Valera, G. N. da Silva, H. F. de Oliveira, C. A. Scrideli, K. Umezawa, L. G. Tone: Cytostatic in vitro effects of DTCM-glutarimide on bladder carcinoma cells. Asian Pacific Journal of Cancer Prevention 13: 1957-1962, 2012.

18. M. Nakayama, Y. Niki, T. Kawasaki, Y. Takeda, K. Horiuchi, A. Sasaki, Y. Okada, K. Umezawa, H. Ikegami, Y. Toyama and T. Miyamoto: Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha. Arthritis Research & Therapy 14:R120 http://arthritis-research.com/content/14/3/R120, 2012.

19. R. Kobayashi, K. Hanaya, M. Shoji, K. Umezawa and T. Sugai: A chemo-enzymatic expeditious route to racemic dihexanoyl (2R*,3R*,4R*)-dehydroxymethylepoxyquinomycin (DHMEQ), the precursor for lipase-catalyzed synthesis of the potent NF-kappa B Inhibitor, (2S,3S,4S)-DHMEQ. Chemical and Pharmaceutical Bulletin 60: 1220-1223, 2012.

20. A. M. Castro-Gamero, K. S. Borgesa, V. da Silva Silveira, R. C. P. Lira, R. de Paula G. Queiroz, F. C. P. Valera, C. A. Scrideli, K. Umezawa and L. G. Tone: Inhibition of nuclear factor-kappaB by dehydroxymethylepoxyquinomicin induces schedule-dependent chemosensitivity to anticancer drugs and enhances chemoinduced apoptosis in osteosarcoma cells. Anti-Cancer Drugs 2012: 638-650, 2012.

21. F. C.P. Valera, K. Umezawa, M. S. Brassesco, A. M. C. Gamero, R. G. P. Queiro, C. A. Scrideli, L. G. Tone, W. T. Anselmo-Lima: Suppression of inflammatory cytokine secretion by an NF-kappa B inhibitor in nasal polyps fibroblasts. Cellular Physiology and Biochemistry 30: 13-22, 2012.

22. N. Kozakai, E. Kikuchi, M. Hasegawa, E. Suzuki, H. Ide, A. Miyajima, Y. Horiguchi, J. Nakashima, K. Umezawa, N. Shigematsu and M. Oya: Enhancement of radiosensitivity by a unique novel NF-kappa B inhibitor, DHMEQ, in prostate cancer. British J. Cancer 107: 652-657, 2012.

23. Y. Niwa, T. Suzuki, N. Dohmae, K. Umezawa and S. Simizu: Determination of cathepsin V activity and intracellular trafficking by N-glycosylation. FEBS Lett. 586: 3601–3607, 2012.

24. M. Nishimura, T. Nii, G. Trimova, S. Miura, K. Umezawa, A. Ushiyama, T. Kubota: The NF-kappa B specific inhibitor DHMEQ prevents thrombosis formation in a mouse model of antiphospholipid syndrome. J. Nephropathology 2 (2):114-121, 2013.

25. T. Shimo, Y. Adachi, S. Yamanouchi, S. Tsuji, T. Kimata, K. Umezawa, M. Okigaki, J. Takaya, S. Ikehara, K. Kaneko: A novel NF- kappa B inhibitor DHMEQ ameliorates puromycin aminonucleoside induced nephrosis in mice. Am. J. Nephrol. 37: 302–309, 2013.

26. A. Ogasawara, S. Simizu, A. Ito, T. Kawai, Y. Saisho, I. Takei and K. Umezawa: Inhibition of NO-induced beta-cell death by novel NF-kappa B inhibitor (-)-DHMEQ via activation of Nrf2-ARE pathway. Biochem. Biophys. Chem. Commun. 433: 181–187, 2013.

27. K. Sidthipong, S. Todo, I. Takei, I. Kojima and K. Umezawa: Screening of new bioactive metabolites for diabetes therapy (Review). Intern. Emerg. Med. 8 (Suppl 1): S57-S59, 2013.

28. S. Shibasaki, K. Yamashita, R. Goto, K. Wakayama, Y. Tsunetoshi, M. Zaitsu, R. Igarashi, S. Haga, M. Ozaki, K. Umezawa and S. Todo: Immunosuppressive Effects of DTCM-G, a Novel Inhibitor of the mTOR Downstream Signaling Pathway. Transplantation 95: 542-550, 2013.

29 K. Suzuki, K. Aiura, S. Matsuda, O. Itano, O. Takeuchi, K. Umezawa, and Y. Kitagawa: Combined effect of dehydroxymethylepoxyquinomicin and gemcitabine in a mouse model of liver metastasis of pancreatic cancer. Clinical & Experimental Metastasis 30:381-392, 2013.

30. Y. Arai, H. Iinuma, Y. Ikeda, M. Igarashi, K. Hatano, N. Kinoshita, T. Ukaji, S. Simizu and K. Umezawa: Migracins A and B, new inhibitors of cancer cell migration, produced by Streptomyces sp. J. Antibiot. 66: 225–230, 2013.

31. M. S. Brassesco, J. A. Pezuk, J. C. de Oliveira, E. T. Valera, H. F. de Oliveira, C. A. Scrideli, K. Umezawa and L. G. Tone: Activator Protein-1 Inhibition by 3-[(dodecylthiocarbonyl)methyl]-glutamaride impairs invasion and radiosensitizes osteosarcoma cells in vitro. Cancer Biotherapy and Radiopharmaceuticals 28: 351-358, 2013.

32. M. S. Brassesco, G. Roberto, A. Morales, J. de Oliveira, L. E. Delsin, J. A. Pezuk, E. T. Valera, C. G. Carlotti Jr., E. M. Rego, H. F. de Oliveira, C. A. Scrideli, K. Umezawa and L. G. Tone: Inhibition of NF-kappa B by dehydroxymethylepoxyquinomicin suppresses invasion and synergistically potentiates Temozolomide and g-radiation cytotoxicity in glioblastoma cells. Chemotherapy Research and Practice, Volume 2013 Article ID 593020 (16 pages), 2013.

33. K. Umezawa: Peritoneal NF-kappa B as a possible molecular target for suppression of various cancers and inflammation. (Review) Forum of Immunopathological Diseases and Therapeutics 4: 63-77, 2013.

34. S. Nakajima, H. Kato, L. Gu, S. Takahashi, H. Johno, K. Umezawa and M. Kitamura: Pleiotropic potential of dehydroxymethylepoxyquinomicin for NF-kappa B suppression via reactive oxygen species and unfolded protein response. J. Immunol. 190: 6559-6569, 2013.

35. M. Kassan, S. K. Choi, M. Galán, A. Bishop, K. Umezawa, M. Trebak, K. Matrougui: NFkappaB impairs vascular function through PARP-1, SP-1 and COX2-dependent mechanisms in type 2 diabetes. Diabetes 62: 2078-2087, 2013.

36. T. Ohsugi, T. Ishida, T. Shimasaki, S. Okada and K. Umezawa: p53 dysfunction precedes the activation of nuclear factor-kappa B during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein. Carcinogenesis 34: 2129-2136, 2013.

37. M. Kuroda, S. Funasaki, T. Saitoh, Y. Sasazawa, S. Nishiyama, K. Umezawa and S. Simizu: Determination of topological structure of ARL6ip1 in cells: Identification of the essential binding region of ARL6ip1 for conophylline. FEBS Letters 587: 3656-3660, 2013.

38. T. Togano, M. Nakashima, M. Watanabe, K. Umezawa, T. Watanabe, M. Higashihara and R. Horie: Synergistic effect of 5-azacytidine and NF-kappa B inhibitor DHMEQ on apoptosis induction in myeloid leukemia cells. Oncology Res. 20: 571-577, 2013.

39. N. Sukumwang and K. Umezawa: Earthworm-derived pore-forming toxin Lysenin and screening of its inhibitors. Toxins 5: 1392-1401, 2013.

40. T. Ukaji, S. Gantsev and K. Umezawa: Inhibition of Cancer cell invasion and metastasis by NF-kappa B inhibitors. (Review) Creative Surgery and Oncology 2013 (3): 6-12, 2013.

41. S. K. Gantsev, K. Umezawa, D. V. Islamgulov, E. K. Husnutdinova, R. S. Ishmuratova, V. Y. Frolova, S. R. Kzyrgalin: The role of inflammatory chemokines in lymphoid neoorganogenesis in breast cancer. Biomedicine & Pharmacotherapy 67: 363-366, 2013.

42. D. Kuraya, M. Watanabe, Y. Koshizuka, M. Ogura, T. Yoshida, Y. Asahi, H. Kamachi, T. Nakamura, H. Harashima, M. Ozaki, K. Umezawa, M. Matsushita, K. Yamashita, and S. Todo: Efficacy of DHMEQ, a NF-kappa B Inhibitor, in islet transplantation: I. HMGB1 suppression by DHMEQ prevents early islet graft damage. Transplantation 96: 445-453, 2013.

43. H. Kono, K. Nakagawa, S. Morita, K. Shinoda, R. Mizuno, E. Kikuchi, A. Miyajima, K. Umezawa and M. Oya: Effect of a novel nuclear factor kappaB activation inhibitor on renal ischemia reperfusion injury. Transplantation 96: 863-870, 2013.

44. M. Watanabe, K. Yamashita, H. Kamachi, D. Kuraya, Y. Koshizuka, S. Shibasaki, Y. Asahi, H. Ono, S. Emoto, M. Ogura, T. Yoshida, M. Ozaki, K. Umezawa, M. Matsushita and S. Todo: Efficacy of DHMEQ, an NF-kappa B inhibitor, in islet transplantation: II. Induction DHMEQ treatment ameliorates subsequent alloimmune responses and permits long-term islet allograft acceptance. Transplantation 96: 454-462, 2013.

45. 梅澤一夫:糖尿病治療に有用なシグナル伝達阻害剤の探索と分子デザイン。Screening and molecular design of signal transduction inhibitors for diabetes therapy. 日本糖尿病眼学会誌 18: 13-19, 2013.

46. N. Kubo, R. Saito, K. Hamano, M. Nagasawa, F. Aoki, I. Takei, K. Umezawa, H. Kuwano and I. Kojima: Conophylline suppresses hepatic stellate cells and attenuates thioacetamide-induced liver fibrosis in rats. Liver International 2013, DOI: 10.1111/liv.12328.

47. S. Shimogaki, S. Ito, S. Komatsu, R. Koike, N. Miyasaka, K. Umezawa and T. Kubota: Inhibition of the NF-kappa B pathway as a candidate therapeutic strategy for cryopyrin-associated periodic syndrome. Mod. Rhumatol. 24: 517-524. doi: 10.3109/14397595.2013.844298. Epub 2013 Nov 4.

48. T. Ukaji, Y. Sasazawa, K. Umezawa and S. Simizu: Involvement of conserved tryptophan residues for secretion of TIMP-2. Oncology Letters 7: 631-634, 2014.

49. T. Togano, M. Watanabe, K. Itoh, K. Umezawa, N. Masuda, M. Higashihara and R. Horie: Activation of Akt involves resistance to NF-kappa B inhibition and abrogation of both triggers synergistic apoptosis in lung adenocarcinoma cells. Lung Cancer 83: 139-145, 2014.

50. M. Watanabe, K. Umezawa, M. Higashihara and R. Horie: Combined inhibition of NF-kappa B and Bcl-2 triggers synergistic reduction of viability and induces apoptosis in melanoma cells. Oncology Res. 21: 173-180, 2014.

51. Y. Goto, Y. Niwa, T. Suzuki, N. Dohmae, K. Umezawa and S. Simizu: C-mannosylation of human hyaluronidase 1: Possible roles for secretion and enzymatic activity. International J. Oncology 45: 344-350, 2014.

52. M. El-Salhy, K. Umezawa, O.-H. Gilja, J. G. Hatlebakk, D. Gundersen and T. Hausken: Amelioration of severe TNBS induced colitis by novel AP-1 and NF-kappa B inhibitors in rats. The Scientific World Volume 2014 Article ID 813804 (8 pages)

53. M. Celegato, C. Borghese, K. Umezawa, N. Casagrande, A. Colombatti, A. Carbone, and D. Aldinucci: The NF-kappa B inhibitor DHMEQ decreases survival factors, overcomes the protective activity of microenvironment and synergizes with chemotherapy agents in classical Hodgkin lymphoma. Cancer Letters 349: 26-34, 2014.

54. H. Nishio, T. Yaguchi, J. Sugiyama, H. Sumimoto, K. Umezawa, T. Iwata, N. Susumu, T.Fujii, N. Kawamura, A. Kobayashi, J-H Park, D. Aoki, Y. Kawakami: Immunosuppression through constitutively activated NF-kappa B signaling in human ovarian cancer and its reversal by a NF-kappa B inhibitor. British J. Cancer 110: 2965-2974, 2014.

55. M. Sato, K. Nakanishi, S. Haga, M. Fujiyoshi, M. Baba, K. Mino, Yimin, H. Niwa, H. Yokoo, K. Umezawa, Y. Ohmiya, T. Kamiyama, S. Todo, A. Taketomi and M. Ozaki: Anoikis induction and inhibition of peritoneal metastasis of pancreatic cancer cells by a nuclear factor-kappa B inhibitor, (-)-DHMEQ. Oncology Res. 21: 333-343, 2014..

56. T. Ukaji and K. Umezawa: Novel approaches to target NF-kappa B and other signaling pathways in cancer stem cells. Advances in Biological Regulation 56: 108-115, 2014.

57. N. Koide, Y. Kondo, E. Odkhuu, J. Ulziisaikhan, T. Ukaji, T. Yokochi and K. Umezawa: Inhibition of receptor activator of nuclear factor-kappa B ligand (RANKL) or lipopolysaccharide-induced osteoclast formation by conophylline (CNP) through downregulation of CREB. Immunology Letters 161: 31-37, 2014.

58. C. Matsui, Y. Ikeda, H. Iinuma, N. Kushida, T. Kunisada, S. Simizu and K. Umezawa: Isolation of a novel paxilline analog pyrapaxilline from fungus that inhibits LPS-induced NO production. J. Antibiotics 67: 787-790, 2014.

59. S. Haga, T. Ozawa, Y. Yamada, N. Morita, I. Nagashima, H. Inoue, Y. Inaba, N. Noda, R. Abe, K. Umezawa and M. Ozaki: p62/SQSTM1 plays a protective role in oxidative injury of steatotic liver in a mouse hepatectomy model. Antioxidants and Redox Signaling 18: 2515-2530, 2014.

60. N. Lampiasi, K. Umezawa, G. Montalto, M. Cervello: Poly (ADP-Ribose) polymerase inhibition synergizes with the NF-kappa B inhibitor DHMEQ to kill hepatocellular carcinoma cells. BBA - Molecular Cell Research 1843: 2662-2673, 2014.

61. T. Miyagi, B. Shiotani, R. Miyoshi, T. Yamamoto, T. Oka, K. Umezawa, T. Ochiya, M. Takano and H. Tahara: DSE-FRET: A new anti-cancer drug screening assay for DNA binding proteins. Cancer Science 105: 870-874, 2014.

62. W. Seubwai, R. Kraiklang, K. Vaeteewoottacharn, K. Umezawa, S. Okada, S. Wongkham: Aberrant expression of NF-kappa B in liver fluke associated cholangiocarcinoma: implications for targeted therapy. PLOS ONE 9 (8): e106056, 2014.

63. M. Kamoshita, Y. Ozawa, S. Kubota, S. Miyake, C. Tsuda, N. Nagai, K. Yuki, S.  Shimmura, K. Umezawa and K. Tsubota. AMPK-NF-kappa B axis in the photoreceptor disorder during retinal inflammation. PLoS One 9 (7): e103013, 2014.

64. S. Inokawa, T. Watanabe, H. Keino, Y. Sato, A. Hirakata, A. A. Okada, K. Fukuda, A. Fukushima and K. Umezawa: Dehydroxymethylepoxyquinomicin, a novel nuclear factor–kappa B inhibitor, reduces chemokines and adhesion molecule expression induced by IL-1beta in human corneal fibroblasts. Graefes Arch. Clin. Exp. Ophthalmol. 253: 557-563, 2015

65. M. Kuboki, A. Ito, S. Simizu and K. Umezawa: Activation of apoptosis by caspase-3-dependent specific RelB cleavage in anticancer agent-treated cancer cells: Involvement of positive feedback mechanism. Biochem. Biophys. Res. Commun. 456: 810–814, 2015.

66. N. Koide, A. Kaneda, T. Yokochi and K. Umezawa: Inhibition of RANKL- and LPS-induced osteoclast differentiations by novel NF-kappa B inhibitor DTCM-glutarimide. International Immunopharmacology 25: 162-168, 2015.

67. K. Horie, J. Ma and K. Umezawa: Inhibition of canonical NF-kappa B nuclear localization by (-)-DHMEQ via impairment of DNA binding. Oncology Res. 22: 105-115, 2015.

68. N. Noma, M. Asagiri, M. Takeiri, S. Ohmae, K. Takemoto, K. Iwaisako, S. Simizu and K. Umezawa: Inhibition of MMP-2-mediated mast cell invasion by NF-kappa B inhibitor DHMEQ in mast cells. International Achieves of Allergy and Immunology 166: 84-90, 2015.

69. J. C. Mbongue, D. Nicholas, K. Zhang, B. N. Hamilton, M. Larios, G. Zhang, K. Umezawa, A. Firek and W. H. R. Langridge: Induction of indoleamine 2, 3 dioxygenase in human dendritic cells by a cholera toxin B subunit - Proinsulin vaccine. PLOS ONE DOI: 10.1371/journal.pone.0118562, 2015.

70. Y. Sasazawa, N. Sato, K. Umezawa and S. Simizu: Conophylline protects cells in cellular models of neurodegenerative diseases by inducing mTOR-independent autophagy. J. Biol. Chem. 290: 6168-6178, 2015.

71. Y. Ito, E. Kikuchi, N. Tanaka, T. Kosaki, E. Suzuki, R. Mizuno, T. Shinojima, A. Miyajima, K. Umezawa and M. Oya: Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer. BMC Cancer BMC Cancer (2015) 15:324 DOI 10.1186/s12885-015-1315-9.

72. M. Zaitsu, K. Yamashita, S. Shibasaki, Y. Tsunetoshi, M. Fukai, M. Ogura, T. Yoshida, R. Igarashi, N. Kobayashi, K. Umezawa and S. Todo: 3-[(dodecylthiocarbonyl)methyl]-glutarimide attenuates graft arterial disease by suppressing alloimmune responses and vascular smooth muscle cell proliferation. Transplantation 99: 948-56, 2015. doi: 10.1097/TP.0000000000000576.

73. S. Yamanouchi, Y. Adachi, T. Shimo, K. Umezawa, M. Okigaki, S. Tsuji, M Li, J. Takaya, T. Kuge, S. Ikehara, K. Kaneko: A nuclear factor-kB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates GVHD in allogeneic bone marrow transplantation. Immunobiology 220: 1059-1066, 2015.

74. T. Toda, M. Watanabe, J. Kawato, M. Higashihara, T. Kunisada, K. Umezawa and R. Horie: Brefeldin A exerts differential effects on anaplastic lymphoma kinase positive anaplastic large cell lymphoma and Hodgkin lymphoma cell lines. British J. Haematology 170: 837-846, 2015.

75.T. F. S. Ali, K. Iwamura, H. I. Ciftci, R. Koga, M. Matsumoto, Y. Oba, H. Kurosaki, M. Fujita, Y. Okamoto, K. Umezawa, M. Nakao, T. Hide, K. Makino, J. Kuratsu, M. Abdel-Aiziz, G. El-Din, A. A. Abuo-Rahma, E. A. M. Beshr and M. Otsuka: Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine–pyridine– histidine system. Bioorg. Med. Chem. 23: 5476-5482, 2015.

76. T. Ukaji, Y. Lin, K. Banno, S. Okada and K. Umezawa: Inhibition of IGF-1-mediated cellular migration and invasion by migracin A in ovarian clear cell carcinoma cells. PLOS One 10(9): e0137663, 2015 DOI:10.1371/journal.pone.0137663.

77. L. Wang, Y. Lin, K. Sidthipong, J. Tang, M. Li, T. Koyano, T. Kowithayakorn, K. Sumiyoshi, T. Ukaji, and K. Umezawa: Inhibition of NF-kB and cellular invasion by novel flavonoid desmal in ovarian carcinoma cells. Heterocycles 92: 353-360, 2016.

78. W. Seubwai, K. Vaeteewoottacharn, R. Kraiklang, K. Umezawa, S. Okada and S. Wongkham: Inhibition of NF-κB activity enhances sensitivity to anticancer drugs in cholangiocarcinoma cells. Oncology Research 23: 21-28, 2016.

79. M. El-Salhy and K. Umezawa: Treatment with novel AP-1 and NF-κB inhibitors restores the colonic endocrine cells to normal levels in rats with DSS-induced colitis. International J. Molecular Medicine DOI: 10.3892/ijmm.2016.2481.

80. N. Ichikawa, K. Yamashita, T. Funakoshi, S. Ichihara, M. Fukai, M. Ogura, N. Kobayashi, M. Zaitsu, T. Yoshida, S. Shibasaki, Y. Koshizuka, Y. Tsunetoshi, M. Sato, T. Einama, M. Ozaki, K. Umezawa, T. Suzuki and S. Todo: A novel anti-inflammatory agent, DTCM-glutarimide, ameliorates murine models of inflammatory bowel disease. Inflammation Research DOI 10.1007/s00011-015-0911-0, 2016.

81. T. Okamoto, Y. Ozawa, M. Kamoshita, H. Osada, E. Toda, T. Kurihara, N. Nagai, K. Umezawa and K. Tsubota: The neuroprotective effect of rapamycin as a modulator of the mTOR-NF-κB axis during retinal Inflammation. PLOS One published 15 Jan 2016 10.1371/journal.pone.0146517.

82. M. Hirasawa, K. Takubo, H. Osada, S. Miyake, E. Toda, M. Endo, K. Umezawa, K. Tsubota, Y. Oike and Y. Ozawa: Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration. J. Biol. Chem. jbc.M115.710186. First Published on February 2, 2016, doi:10.1074/jbc.M115.710186.

83. M. Morioka, K. Kato, and K. Umezawa: Design and synthesis of 15-deoxyspergualin-biotin conjugates as novel binding probes for target protein screening. J. Antibiotics in press.

84. S. Katsuyama, K. Sugino, Y. Sasazawa, Y. Nakano, H. Aono, K. Morishita, M. Kawatani, K. Umezawa, H. Osada and S. Simizu: Identification of a novel compound that inhibits osteoclastogenesis by suppressing nucleoside transporters. FEBS Letters in press.

85. M. El-Salhy and K. Umezawa: Anti-inflammatory effects of novel AP-1 and NF-κB inhibitors in dextran-sulfate-sodium-induced colitis in rats. International J. Mol. Med. in press.

2012年以降の主な学会発表等(採択済み含む)

1. 梅澤一夫:NF-kappa B阻害剤の発見と臨床への橋渡し研究。文科省がん支援・化学療法基盤支援活動 第2回シンポジウム「アカデミアからの抗がん剤創薬へ向けて」2012.2.22日吉。

2. 梅澤一夫:NF-kappa B阻害剤DHMEQの調製と作用機構。北海道大学医学研究科寄附講座 分子制御外科学講座終了記念シンポジウム 分子標的医薬開発の現状と将来 2012.3.12 札幌。

3. 梅澤一夫:炎症・癌を抑制するシグナル伝達阻害剤の探索と分子デザイン。Screening and molecular design of signal transduction inhibitors active on inflammation and cancer. 名古屋大学医学部グローバルCOE「第31回プログレスレポート会議」

2012.6.5名古屋

4. 村橋将崇,眞井絵里佳,清水史郎,梅澤一夫:免疫抑制剤デオキシスパーガリンの標的分子の探索。Characterization of target proteins for immunosuppressive agent 15-deoxyspergualin. 日本ケミカルバイオロジー学会 2012.6.7-9 京都

5. 舟崎慎太郎,宇梶珠未,Kulrawee Sidthipong,清水史郎,梅澤一夫:植物性アルカロイドconophyllineによる癌細胞薬剤耐性の軽減と標的タンパク質の結合解析。第16回がん分子標的治療学会2012.6.27-29 福岡。

6. Kulrawee Sidthipong and Kazuo Umezawa: Molecular design and cellular activity of new NF-kappa B inhibitors. (Invited speaker) Forum of the Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Thailand 2012.8.29.

7. Kazuo Umezawa: Screening of cellular signaling inhibitors active on cancer and diabetes: Recent results. (Invited speaker) Forum of the Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Thailand 2012.8.29.

8. 伊藤あゆみ,清水史郎,梅澤一夫: DTCM-glutarimideによる成人T細胞白血病におけるRelBの分解とアポトーシス誘導。Ayumi Ito, Siro Simizu, and Kazuo Umezawa: Induction of RelB degradation and apoptosis in adult T-cell leukemia cells by DTCM-glutarimide.日本癌学会 2012.9.19-21 札幌

9. 後藤祐貴,丹羽祐貴,鈴木健裕,堂前直,梅澤一夫,清水史郎:C-mannosylation hyaluronidase1 機能に与える影響。Yuki Goto, Yuki Niwa, Takahiro Suzuki, Naoshi Dohmae, Kazuo Umezawa, and Siro Simizu: Role of C-mannosylation on hyaluronidase1 functions. 日本癌学会 2012.9.19-21 札幌

10. K. Umezawa, S. Simizu, S. Funasaki, K. Sidthipong, R. Saito, and I. Kojima: Inhibition of islet fibrosis by conophylline and analysis of target protein. The 17th World Congress on Advances in Oncology, and 15th International Symposium on Molecular Medicine, 2012.10.11-13, Crete, Greece.

11. K. Horie, M. Takeiri, S. Simizu, and K. Umezawa: Inhibition of canonical and noncanonical NF-kappa Bs by (-)-DHMEQ. The 17th World Congress on Advances in Oncology, and 15th International Symposium on Molecular Medicine, 2012.10.11-13, Crete, Greece.

12. 梅澤一夫:糖尿病に有用なシグナル伝達阻害剤の探索と分子デザイン。(Meet the Professor 招待講演)第18回日本糖尿病眼科学会総会。第27回日本糖尿病合併症学会。2012.11.2-3 福岡。

13. Kazuo Umezawa: Anti-diabetic and anti-fibrosis effect of plant-derived conophylline. (Invited speaker) Tuscany Endocrinology and Metabolism Conference 2013.4.5-6 Pisa, Italy.

14. Kulrawee Sidthipong and Kazuo Umezawa: Amelioration of islet transplantation in diabetes by NF-kappa B inhibitors. (Invited speaker) Tuscany Endocrinology and Metabolism Conference 2013.4.5-6 Pisa, Italy.

15. 松井知野,丹羽祐貴,Neelanun Sukumwan,飯沼寛信,池田洋子,小谷野喬,Thaworn Kovitayakorn,清水史郎,梅澤一夫:植物由来All-E-Luteinによるライセニンに誘導される溶血の抑制。新規素材探索研究会 2013.6.7新横浜

16. 野間成人,清水史郎,梅澤一夫:NF-kappa B阻害剤(-)-DHMEQMMP-2依存性のマスト細胞浸潤を抑制する。第17回がん分子標的治療学会2013.6.12-14 京都。

17. Kulrawee Sidthipong,宇梶珠未,梅澤一夫:新規(-)-DHMEQ誘導体の分子デザインとサイトカイン分泌の抑制。(ポスター賞受賞)第17回がん分子標的治療学会2013.6.12-14京都。

18. 宇梶珠未,Kulrawee Sidthipong,小林進,梅澤一夫:新規 epoxide-free (-)-DHMEQ 誘導体の分子デザインとサイトカイン分泌の抑制。日本ケミカルバイオロジー学会 2013.6.19-21 東京。

19. 笹澤有紀子,梅澤一夫,清水史郎:Conophyllineによるオートファジー誘導。日本ケミカルバイオロジー学会 2013.6.19-21 東京。

20. K. Umezawa, T. Ukaji, A. Ogasawara, S. Simizu and I. Takei: Suppression of NO-induced beta cell death by (-)-DHMEQ via activation of Nrf2-ARE pathway and alteration of MAPK activity. (invited speaker) 49th Annual European Association for the Study of Diabetes (EASD) Meeting 2013 2013.9.23-27 Barcelona, Spain.

21. 宇梶 珠未,竹入 雅敏,伊藤 あゆみ,清水 史郎, 梅澤 一夫:新規alkylglutarimide化合物による成人T細胞白血病細胞のNF-kappa B阻害と選択的アポトーシス誘導。Inhibition of NF-kappa B and induction of selective apoptosis by novel alkylglutarimide compounds in adult T-cell leukemia cells. 日本癌学会2013.10.3-5 横浜。

22. Tamami Ukaji, Kulraweee Sidthipong, and Kazuo Umezawa: Molecular design of novel NF-kappa B inhibitors active on inflammation and cancer. The 2nd Official Conference of the International Chemical Biology Society (ICBS2013), 2013.10.7-9, Kyoto.

23. K. Umezawa and I. Takei: Protection of beta-cells from cell death by NF-kappa B inhibitor (-)-DHMEQ via activation of Nrf2-ARF pathway. (invited speaker) The 18th World Congress on Advances in Oncology, and 16th International Symposium on Molecular Medicine, 2013.10.10-12, Crete, Greece.

24. K. Sidthipong, S. Kobayashi and K. Umezawa: Molecular design of epoxide-free (-)-DHMEQ analog that inhibits NF-kappa B and cytokine secretions. (K.S. invited speaker) The 18th World Congress on Advances in Oncology, and 16th International Symposium on Molecular Medicine, 2013.10.10-12, Crete, Greece.

25. Kazuo Umezawa: Biological activities of plant-derived conophylline in vitro and in vivo. (invited speaker) 9回延世慶應ジョイントシンポジウム 2013.10.25, Seoul, Korea.

26. Kazuo Umezawa: Anti-inflammatory and anticancer activities of novel NF-kappa B inhibitor DHMEQ (invited speaker). Eurasian Anticancer Conference, 2013.11.22-23, Ufa, Russia.

27. 梅澤一夫:植物成分コノフィリンによる組織線維化の抑制。(シンポジウム招待講演)中部橋渡し研究支援シンポジウム2014.3.6 名古屋。

28. 梅澤一夫:シグナル伝達阻害剤の探索・応用と出口戦略。(特別講演)生物化学研究室25周年記念シンポジウム 2014.4.26 横浜。

29. Tamami Ukaji and Kazuo Umezawa: Isolation of novel metabolite migracin from Streptomyces that inhibits migration and invasion of ovarian carcinoma cells. 3rd Regional International Gynecologic Cancer Society (IGCS) Meeting 2014, 2014.5.16-18 Cape Town, South Africa

30. 梅澤一夫:低分子シグナル伝達阻害剤の探索とマトリクス修飾への応用。(招待講演)第46回日本結合組織学会学術大会 61回日本マトリクス研究会大会 合同集会 2014.6.5-7 名古屋。

31. 宇梶珠未,梅澤一夫:微生物由来新規細胞遊走阻害物質migracinの単離と卵巣がん細胞浸潤の抑制。日本ケミカルバイオロジー学会 2014.6.11-13 大阪。

32. 佐藤夏実,笹澤有紀子,梅澤一夫,清水史郎:Conophyllineの抗ハンチントン病作用。日本ケミカルバイオロジー学会 2014.6.11-13 大阪。

33. 宇梶珠未,梅澤一夫:放線菌由来新規がん細胞遊走阻害物質migracinの単離と卵巣がん細胞浸潤の抑制。(口演)第18回がん分子標的治療学会2014.6.25-27 仙台。

34. Kulrawee Sidthipong,梅澤一夫:新規NF-kappa B阻害剤Exo-ene EQによる卵巣がん細胞の浸潤抑制。(口演)第18回がん分子標的治療学会2014.6.25-27 仙台。

35. 宇梶珠未、梅澤 一夫:放線菌由来新規細胞遊走阻害物質migracinの単離と管腔形成およびがん細胞浸潤の抑制。Isolation of novel cell migration inhibitor migracin from Streptomyces and suppression of lumina formation and cancer cell invasion. 日本癌学会 2014.9.25-27 横浜。

36. Kulrawee Sidthipong and Kazuo Umezawa: Suppression of cellular invasion by novel NF-kappa B inhibitor Exo-ene EQ in ovarian carcinoma cells. (KS, invited speaker) The 19th World Congress on Advances in Oncology, and 17th International Symposium on Molecular Medicine, 2014.10.9-11, Athens, Greece.

37. Kazuo Umezawa: Inhibition of cancer cell invasion by bioactive metabolites.

(invited speaker) The 19th World Congress on Advances in Oncology, and 17th International Symposium on Molecular Medicine, 2014.10.9-11, Athens, Greece.

38. Kazuo Umezawa: Suppression of cellular invasion by novel NF-kappa B inhibitor Exo-ene EQ in ovarian carcinoma cells. (invited speaker) 10回延世慶應ジョイントシンポジウム 2014.10.24 Yokohama.

39. Kulrawee Sidthipong, 小林進、梅澤一夫: 新規epoxide-free (-)-DHMEQ誘導体の

分子デザイン・合成と抗炎症活性。第56回天然有機化合物討論会 2014. 10. 15-17 高知。

40. Kazuo Umezawa: Screening of signal transduction modulators that inhibit cancer cell growth and spread. (invited speaker) DSK Mini-Symposium-Perspectives in Anticancer Drug Discovery and Development. 2014.11.11 Kyoto.

41. 梅澤一夫: 糖尿病治療に有用な低分子シグナル伝達阻害剤の探索と分子デザイン。(招待講演)Diabetes Research フォーラム 2014.11.26 幕張。

42. 梅澤一夫、渡辺秀人、米田政志:糖尿病や肝硬変を改善する植物成分。(展示と発表)メディカルメッセ 2014.2.16 名古屋市中小企業振興会館(吹上)。

43. Tamami Ukaji and Kazuo Umezawa: Isolation of novel cell migration inhibitor migracins from Streptomyces and inhibition of cellular invasion in ovarian carcinoma cells. 13th International Congress on Targeted Anticancer Therapies 2015.3.2-4, Paris.

44. 梅澤一夫:新しいNF-kappa B阻害剤、がん細胞浸潤阻害剤、組織線維化阻害剤の探索と生物活性。戦略的研究基盤形成支援事業公開シンポジウム 2014.3.13 愛知医科大学。

45. Kazuo Umezawa: Discovery of DHMEQ and the role of peritoneal NF-kappa B on diseases. BRICS Symposium “Development of DHMEQ in BRICS countries” 2015.6.4-6, Ufa, Russia.

46. Kulrawee Sidthipong, Susumu Kobayashi, Kazuo Umezawa: Discovery and biological activity of epoxide-free DHMEQ analog: Compound of second generation BRICS Summit Satellite Symposium “Development of DHMEQ in BRICS countries” 2015.6.4-6, Ufa, Russia.

47. 宇梶珠未、林音知、梅澤一夫:放線菌由来migracin Aによるvasohibin発現を介した卵巣がん細胞遊走の抑制。19回がん分子標的治療学会2015.6.10-12松山。

48. 梅澤一夫、小出直樹:LPS誘導性炎症反応を阻害する微生物生産物質の探索。第62回トキシンシンポジウム 2015.7.8-10 伊勢志摩。

49. 宇梶珠未、Lin Yinzhi、梅澤一夫:放線菌由来新規がん細胞遊走阻害物質migracinの発見と卵巣がん細胞における遊走・浸潤抑制の作用機構。第57天然有機化合物討論会2015.9.9-11横浜。

50. Tamami Ukaji and Kazuo Umezawa: 卵巣がん細胞におけるmigracin AによるIGF-1発現および遊走・浸潤の抑制。Inhibition of IGF-1 mediated cellular migration and invasion by migracin A in ovarian carcinoma cells. (口演)第74回日本癌学会 2015.10.8-10 名古屋。

51. Tamami Ukaji and Kazuo Umezawa: Inhibition of IGF-1 mediated cellular migration and invasion by migracin A in ovarian clear cell carcinoma cells. European Gynecological Oncology Congress 2015.10.24-27, Nice, France.

52. Kulrawee Sidthipong and Kazuo Umezawa: NF-kappa B inhibitor, (-)-DHMEQ, as an anti-inflammatory agent in cosmetics. (Oral presentation for 1st Palce Poster Prize) 10thWorld Congress of the International Academy of Cosmetic Dermatology 2015.11.14-16, Rio de Janeiro, Brazil.

53. K. Umezawa: Inhibition of endotoxin shock model by IP therapy with DHMEQ and other recent results in Aichi Medical University. (invited speaker) Bashkortostan-Aichi Joint Seminar "Suppression of endotoxin shock and cancer by novel bioactive metabolites" 2016.1.14-15, Ufa Russia.

54. Yinzhi Lin and Kazuo Umezawa: Inhibition of NF-kB and cancer cell invasion by novel flavonoid, desmal. (invited speaker) Bashkortostan-Aichi Joint Seminar "Suppression of endotoxin shock and cancer by novel bioactive metabolites" 2016.1.14-15, Ufa Russia.

55. Tamami Ukaji and Kazuo Umezawa: Inhibition of IGF-1-mediated cellular migration and invasion by migracin A in ovarian clear cell carcinoma cells. AACR-JCA 10th Joint Conference in Hawaii 2016.2.16-20. Maui, USA.

56.宇梶珠未、Yinzhi Lin、梅澤一夫NF-kB阻害剤DHMEQによる3Dがん細胞浸潤の抑制と機構解析。20回がん分子標的治療学会2016.5.30-6.1別府、大分。

57. Yinzhi Lin、宇梶珠未、梅澤一夫:放線菌由来細胞遊走・浸潤阻害物質migracinの単離と作用機構。新規素材研究会 2016.6.3 横浜。

58. 宇梶珠未、Yinzhi Lin、梅澤一夫:微生物由来migracin AによるIGF-1発現抑制を介した卵巣がん細胞遊走・浸潤の阻害。日本ケミカルバイオロジー学会 2016.6.15-17 京都。

59. Kulrawee Sidthipong小出直樹、梅澤一夫:微生物および植物由来LPS機能阻害物質の探索(若手奨励講演)第63回トキシンシンポジウム 2016.7.14-16 天童、山形。

60. Tamami Ukaji and Kazuo Umezawa: NF-kB阻害剤DHMEQによるMMPを介した3D乳がん細胞浸潤の抑制。Inhibition of MMP-mediated 3D breast cancer cell invasion by NF-kB inhibitor DHMEQ. 75回日本癌学会 2016.10.8-10 横浜。


キーワード

分子標的医薬,炎症,癌,糖尿病,シグナル伝達,天然物,分子デザイン

連絡先

TEL
外線 : 0561-62-3311(代表) / 0561-61-1959(梅澤居室)
内線 : 12211,12376
FAX
0561-61-1959
E-mail
umezawa@aichi-med-u.ac.jp

さらに詳細な情報はこちらで紹介しています

シグナル伝達阻害剤探索研究の概要と私たちの成果(学外)