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Search for cell-death inducing antitumor agents based on the anti-tumor activity of V-ATPase inhibitors

Research Project

Project/Area Number 10557221
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Biological pharmacy
Research InstitutionKanazawa University

Principal Investigator

OHKUMA Shoji  Pharmaceutical Sciences, Kanazawa University Professor, 薬学部, 教授 (10119563)

Co-Investigator(Kenkyū-buntansha) SOMEI Masanori  Pharmaceutical Sciences, Kanazawa University Professor, 薬学部, 教授 (20110546)
YOKOYAMA Ken  Pharmaceutical Sciences, Kanazawa University Assistance, 薬学部, 助手 (70271377)
ARAI Kunizo  Pharmaceutical Sciences, Kanazawa University Assistant Professor, 薬学部, 講師 (50126562)
HATANAKA Yasumaru  Toyama Medical Phamaseutical University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (30111181)
OHTA Tetsuo  Pharmaceutical Sciences, Kanazawa University Associate Professor, 医学部・附属病院, 助教授 (09671290)
永井 和夫  東京工業大学, 生命理工学部, 教授 (00011974)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1999: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1998: ¥7,000,000 (Direct Cost: ¥7,000,000)
Keywordsbafilomycins / V-ATPase / PC12 / apoptosis / nurite outgrowth (NOG) / prodigiosins / cell-differentiation / concanamycins / 突起伸展 / デストラキシン
Research Abstract

In this project, we have investigated the mechanism of incuction of neurite outgrowth (NOG), cell differentiation, growth inhibiton and apoptosis by inhibitors against V-ATPases, such as bafilomycin, concanamycins and prodigiosins, and the mechanism of proton transport in V-ATPases.
We found that (1) V-ATPase inhibitors like bafilomycin induced apoptosis and NOG in new RNA-, protein-syntheses, and serine/threonine kinase-dependent mannaer, and K-252a- or A-kinase-independent manner, but they are different from each other : apoptosis-induction is different from NOG-induction in its insensitivitiy in tyrosin-phosphatase, arachidonate-cascade or Calmodulin-kinase independent manner, (2) apoptosis and NOG are also induced by prodigiosins but they are not induced by its H^+/Cl^- symporting activities, and (3) apoptosis or NOG is not induced by pH-differences between inside and outside of cells, because they are not induced by NH_4Cl, (4) We have succeeded in the synsesis of concanamycin A-photoaffinity probes active in V-ATPase-inhibition. (5) Prodigiosins are H^+/Cl^- symporters that uncoupled ATPases like F-, V-, P-ATPase and electron transport activity, in which prodigiosins inhibited proton-transport but no ATP hydrolysis (or electron transport) activiteis. Prodigiosins also strongly and reversibly uncoupled (H^+/K^+) ATPase-dependent proton-translocation from hog gastric mucosa. (6) We have succeeded in the cloning, proton-pump dependent ATP synthesis, and determation of operon structure of V-ATPase from a eubacterium (Thermus termophilus).

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (46 results)

All Other

All Publications (46 results)

  • [Publications] Matsuya,H.: "Reversible and potent uncoupling of hog gastric (H^++K^+)-ATPase by prodigiosins."Biochem.Pharmacol.. 60. 1855-1863 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani,H.: "Vacuolar H^+-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts in cultured human saphenous vein."Circulation. 102[suppl III]. 239-274 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishizaki,J.: "Uptake of imipramine in rat liver lysosomes in vitro and its inhibition by basic drugs."J.Pharmacol.Exptl.Therapeut.. 294. 1088-1098 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yokoyama,K.: "V-type ATPase/synthase from Thermus thermophilus -subunit structure and operon-."J.Biol.Chem.. 275. 13955-13961 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani,H.: "Potential role of vacuolar H^+-ATPase in neointimal formation in cultured human saphenous vein."J.Thorac.Cardiovasc.Sur.. 119. 998-1007 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Elnemr,A.: "N-ethylmaleimide-enhanced phosphatidylserine externalization of human pancreatic cancer cells and immediate phosphatidylserine-mediated phagocytosis by macrophages."Intern.J.Oncol.. 16. 1111-1116 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohta,T.: "Activated lansoprazole inhibits cancer cell adhesion to extracellular matrix components."Intern.J.Oncol.. 359. 53-58 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sato,T.: "Prodigiosins as a new group of H^+/Cl^- symporters that uncouple proton translocators."J.Biol.Chem.. 273. 21455-21462 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Konno,H.: "Prodigiosins uncouple mitochondrial and bacterial F-ATPases : evidence for their H^+/Cl^- symport activity."J.Biochem. (Tokyo). 124. 547-556 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohkuma,S,: "Prodigiosins uncouple lysosomal vacuolar-type ATPase through promotion of H^+/ Cl^- symport."Biochem.J.. 334. 731-741 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohta,T.: "Bafilomycin A1 induces apoptosis in human pancreatic cancer cell line capan-1."J.Pathol.. 185. 324-330 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Israel,M.: "Enhanced acetylchholine release from cells that have more 15-kDa proteolipid in their membrane, a constituent V-ATPase, and mediatophore."J.Neurochem. 71. 630-635 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yokoyama,K.: "V-ATPase of Thermus thermophilus is inactivated during ATP hydrolysis but can synthesize ATP."J.Biol.Chem.. 273. 20504-20510 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishizaki,J.: "Uptake of basic drugs into rat lung granue fraction in vitro."Biol.Pharm.Bull.. 21. 858-861 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishizaki,J.: "Influence of ammonium chloride on tissue distribution of anticholinergic drugs in rats"J.Pharm.Pharmacol.. 50. 761-766 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 大熊勝治: "細胞生物学実験法 1.細胞培養法"廣川書店. 154 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuya, H., Okamoto, M., Ochi, T., Nishikawa A., Shimizui, S., Kataoka T., Nagai, K., Wasserman, H.H.and Ohkuma, S.: "Reversible and potent uncoupling of hog gastric (H^++K^+)-ATPase by prodigiosins."Biochem.Pharmacol.. 60. 1855-1863 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani, H., Yamamura, T., Nakao, Y., Hattori, U., Fujii, H., Ninomiya, H., Kido, M., Kawaguchi, H., Osako, M., Imamura, H., Ohta, T., and Ohkuma, S.: "Vacuolar H^+-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts in cultured human saphenous vein."Circulation. 102 [suppl III]. III239-274 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishizaki, J., Yokogawa, K., Ichimura, F., and Ohkuma, S.: "Uptake of imipramine in rat liver lysosomes in vitro and its inhibition by basic drugs."J.Pharmacol.Exptl.Therapeut.. 294. 1088-1098 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yokoyama, K., Ohkuma, S., Taguchi, H., Yasunaga, T., Wakabayashi, T., and Yoshida, M.: "V-type ATPase/synthase from Thermus thermophilus-subunit structure and operon-."J.Biol.Chem.. 275. 13955-13961 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohtani, H., Ohmiya, H., Fujii, H., Ninomiya, H., Kido, M., Kawaguchi, H., Osako, M., Imamura, H., Ohta, T., and Ohkuma, S.: "Potential role of vacuolar H^+-ATPase in neointimal formation in cultured human saphenous vein."J.Thorac.Cardiovasc.Sur.. 119. 998-1007 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Elnemr, A, Ohta, T., Yachie, A., Fushida, S., Ninomiya, I., Nishimura, G.-I., Yamamoto, M., Ohkuma, S., and Miwa, K.: "N-ethylmaleimide-enhanced phosphatidylserine externalization of human pancreatic cancer cells and immediate phosphatidylserine-mediated phagocytosis by macrophages."Intern.J.Oncol.. 16. 1111-1116 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohta, T., Tajima, H., Yachie, A., Yokoyama, K., Elnemr, A., Fushida, S., Kitagawa, H., Kayahara, M., Nishimura, Ge., Miwa, K., Yamamoto, M., Terada, T., and Ohkuma, S.: "Activated lansoprazole inhibits cancer cell adhesion to extracellular matrix components."Intern.J.Oncol.. 359. 53-58 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sato, T., Konno, H., Tanaka, Y., Kataoka, T., Nagai, K., Wasserman, H.H., and Ohkuma, S.: "Prodigiosins as a new group of H^+/Cl^- symporters that uncouple proton translocators."J.Biol.Chem.. 273. 21455-21462 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Konno, H., Matsuya, H., Okamoto, M., Sato, T., Tanaka, Y., Yokoyama, K., Kataoka, T., Nagai, K., Wasserman, H.H., and Ohkuma, S.: "Prodigiosins uncouple mitochondrial and bacterial F-ATPases : evidence for their H^+/Cl^- symport activity."J.Biochem.(Tokyo). 124. 547-556 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohkuma, S., Sato, T., Okamoto, M., Matsuya, H., Arai, K., Kataoka, T., Nagai, K., and Wasserman, H.H.: "Prodigiosins uncouple lysosomal vacuolartype ATPase through promotion of H^+/Cl^- symport."Biochem.J.. 334. 731-741 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohta, T., Arakawa, H., Futagami, F., Tajima, H., Fushida, S., Kitagawa, H., Kayahara, M., Nagakawa, T., Miyazaki, I., Kurashima, K., Numata, M., and Ohkuma, S.: "Bafilomycin A1 induces apoptosis in human pancreatic cancer cell line capan-1."J.Pathol.. 185. 324-330 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Israel, M., Lesbats, B., Tomasi, M., and Ohkuma, S.: "Enhanced acetylchholine release from cells that have more 15-kDa proteolipid in their membrane, a constituent V-ATPase, and mediatophore."J.Neurochem.. 71. 630-635 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yokoyama, K., Muneyuki, E., Amano, T., Mizutani, S., Yoshida, M., Ishida, M., and Ohkuma, S.: "V-ATPase of Thermus thermophilus is inactivated during ATP hydrolysis but can synthesize ATP."J.Biol.Chem.. 273. 20504-20510 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishizaki, J., Yokogawa, K., Nakashima, E., Ohkuma, S., and Ichimura, F.: "Uptake of basic drugs into rat lung granue fraction in vitro."Biol.Pharm.Bull.. 21. 858-861 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishizaki, J., Yokogawa, K., Nakashima, E., Ohkuma, S., Ichimura, F.: "Influence of ammonium chloride on tissue distribution of anticholinergic drugs in rats."J.Pharm.Pharmacol.. 50. 761-766 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hidekazu Matsuya: "Reversible and potent uncoupling of hog gastric (H^++K^+)-ATPase by prodigiosins."Biochem.Pharmacol.. 60. 1855-1863 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hajime Ohtani: "Vacuolar H^+-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts in cultured human saphenous vein."Circulation. 102. III239-274 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Junko Ishizaki: "Uptake of imipramine in rat liver lysosomes in vitro and its inhibition by basic drugs."J.Pharmacol.Exptl.Therapeut.. 294. 1088-1098 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ken Yokoyama: "V-type ATPase/synthase from Thermus thermophilus-subunit structure and operon-."J.Biol.Chem.. 275. 13955-61 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hajime Ohtani: "Potential role of vacuolar H^+-ATPase in neointimal formation in cultured human saphenous vein."J.Thorac.Cardiovasc.Sur.. 119. 998-1007 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tetsuo Ohta: "Activated lansoprazole inhibits cancer cell adhesion to extrancellular matrix components."Intern. J. Oncol.. 15(1). 33-39 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hajime Ohtani: "Potential Role of Vacuolar H+-ATPase in Neointimal Formation in Cultured Human Saphenous Vein"J. Thorac. Cardiovasc. Sur.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ken Yokoyama: "V-type ATPase/synthase from Thermus thermophilus, subunit structure and operon"J. Biol. Chem.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 大熊 勝治: "細胞生物学実験法 I.細胞培養法"廣川書店. 154 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tetsuo Ohta: "Bafilomycin A_1 induces apoptosis in human pancreatic cancer cell line capan-1." J.Pathol.185. 324-330 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shoji Ohkuma: "Prodigiosins uncouple lysosomal vacuolar-type ATPase through promotion of H^+/CI^- symport." Biochem.J.334. 731-741 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Maurice Israel: "Enhanced acetylchholine release from cells that have more 15-kDa protelipid in their membrane,a constituent V-ATPase,and mediatophore." J.Neurochem.71. 630-635 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ken Yokoyama: "V-ATPase of Thermus thermophilus is inactivated during ATP hydrolysis but can synthesize ATP." J.Biol.Chem.273. 20504-20510 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hiroki Konno: "Prodigiosins uncouple mitochondrial and bacterial F-ATPases:evidence for their H^+/Cl^- symport activity." J.Biochem.124. 547-556 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomohiko Sato: "Prodigiosins as a new group of H^+/CI^- symporters that uncople proton translocators." J.Biol.Chem.273. 21455-21462 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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