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Search for new MDR modulator and analysis of its target molecule

Research Project

Project/Area Number 14572004
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionOsaka University

Principal Investigator

AOKI Shunji  Osaka University, Graduate School of Pharmaceutical Sciences, lecturer, 薬学研究科, 講師 (60252699)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsMultidrug resistance tumor cell / P-glycoprotein / MRP1 / agosterol A / radioactive photoaffinity probe / kendarimide A / 光親和性標識
Research Abstract

1) In the course of our study of bioactive substances from majine organisms, we focused on a search for reversing substances of multidrug-resistance (MDR) in tumor cells and isolated agosterol A from a marine sponge Spongia sp. We examined the action of agosterol A for both the P-gp-or MRP1-mediated MDR cells and clalified that agosterol A inhibited the drug transportation through P-gp and/or MRP1 by affecting those drug efflux pumps directly.
2) From the structure-activity relationship study, each of the 3,4,6-acetoxyl groups and 11,22-hydroxyl groups was elucidated to be crucial for reversing MDR in tumor cells. Furthermore, we synthesized the 125I-labeled photoaffinity probe of agosterol A.
3) We succeeded in photolabeling bf MRP1 using the synthtic photoaffinity probe of agosterol A.
Interestingly, the probe showed the affinity to MRP1 only in the presence of glutathione. We found that the probe photolabeled the C-proximal molecule of MRP1 (C932-1531; TMD2). Based on photolabeling studies in the presence and absence of GSH using membrane vesicles expressing various truncated, co-expressed, and mutated MRP1s, we found that LO is the site on MRP1 which interacts with GSH. Furthermore, we demonstrated that the GSH-dependent binding site of the probe lies between amino acid 1223 and 1295, a region of MRP1 which includes'TM helix 17. Furthermore, our findings suggest that the charged amino acid Arg1249 is indispensable for MRP1 substrates interaction whereae the C terminal region (C1295-1531).

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Shunji Aoki, et al.: "Lembehsterols A and B, novel sulfated sterols inhibiting thymidine phosphorylase, form the marine sponge Petrosia strongylata"Chem.Pharm.Bull.. 49. 827-830 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Xiao-Qin Ren, Shunji Aoki, et al.: "Positively Charged Amino Acid proximate to C-terminus of TM17 of MRP1 is Indispensable for GSH-dependent binding of Substrates and for transport of LTC4"Biochemistry. 41. 14132-14140 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Murakami, Shunji Aoki, et al.: "New Rev-transport inhibitor with anti-HIV activity from Valerianae Radix"Bioorg.Med.Chem.Lett.. 12. 2807-2810 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Murakami, Shunji Aoki, et al.: "Facilely accessible multidrug resistance modulator derived from sucrose."Bioorg.Med.Chem.Lett.. 12. 3267-3270 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shunji Aoki, et al.: "Structure-activity relationship of neuritogenic spongean acetylene alcohols, lembehynes."Tetrahedron. 58. 5417-5422 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shunji Aoki, et al.: "Pyridoacridine alkaloids inducing neuronal differentiation in a neuroblastoma cell line, from marine sponge Biemna fortis"Bioorg.Med.Chem.. 11. 1969-1973 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Xiao-Qin Ren, Shunji Aoki, et al.: "Localization of the GSH-dependent photolabelling site of an agosterol A analog on human MRP1."Br J Pharmacol.. 138. 1553-1561 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shunji Aoki, et al.: "In situ photoaffinity labeling of the target protein for lembehyne A, a neuronal differentiation inducer"FEBS Lett.. 544. 223-227 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] M.Mukai, Shunji Aoki, et al.: "Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells."Cancer Sci.. 94. 557-563 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] M.Mitsuo, Shunji Aoki, et al.: "Binding site(s) on P-glycoprotein for a newlysynthesized photoaffinity analog of agosterol A"Oncology Research. 14. 39-48 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] T.Itoh, Shunji Aoki, et al.: "Komodoquinone A, a novel neuritogenic anthracycline, from marine Streptomyces sp. KS3."J Nat Prod.. 66. 1373-1377 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Aoki, Y.Naka, T.Itoh, T.Furukawa, R.Rachmat, S.Akiyama, M.Kobayashi: "Lembehsterols A and B, novel sulfated sterols inhibiting thymidine phosphorylase, from the marine sponge Petrosia strongylata."Chem.Pharm.Bull.. 49. 827-830 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Aoki, K.Matsui, H.Wei, N.Murakami, M.Kobayashi: "Structure-activity relationship of neuri togenic spongean acetylene alcohols, lembehynes."Tetrahedron. 58. 5417-5422 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] X-Q.Ren, T.Furukawa, S.Aoki, T.Sumizawa, M.Haraguchi, Y.Nakajima, R.Ikeda, M.Kobayashi, S.Akiyama, A: "Positively Charged Amino Acid Proximate to the C-terminus of TM17 of MRP1 is Indispensable for GSH-dependent binding of Substrates and for Transport of LTC4"Biochemistry. 41. 14132-14140 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Murakami, Y.Ye, M.Kawanishi, S.Aoki, N.Kudo, M.Yoshida, BE.Nakayama, T.Shioda, M.Kobayashi: "New Rev-transport inhibitor with anti-HIV activity from Valerianae Radix."Biochemistry. 12. 2807-2810 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Murakami, S.Tamura, E.Iwata, S.Aoki, S.Akiyama, M.Kobayashi: "Facilely accessible multidrug resistance modulator derived from sucrose."Bioorg.Med.Chem.Lett.. 12. 3267-3270 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Aoki, H.Wei, K.Matsui, R.Rachmat, M Kobayashi: "Pyridoacridine alkaloids inducing neuronal differentiation in a neuroblastoma cell line, from marine sponge Biemna fortis."Bioorg.Med.Chem.. 11. 1969-1973 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] X-Q.Ren, T.Furukawa, S.Aoki, T.Sumizawa, M.Haraguchi, X-F.Che, M.Kobayashi, S.Akiyama: "Localization of the GSH-dependent photolabelling site of an agosterol A analog on human MRP1."Br J Pharmacol.. 138. 1553-1561 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Aoki, K.Matsui, T.Takata, M.Kobayashi: "In situ photoaffinity labeling of the target protein for lembehyne A, a neuronal differentiation inducer."FEBS Lett.. 544. 223-227 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] M.Mukai, X.F.Che, T.Furukawa, T.Sumizawa, S.Aoki, X.Q.Ren, M.Haraguchi, Y.Sugimoto, M.Kobayashi, H.Takamatsu, S.Akiyama: "Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells."Cancer Sci.. 94. 557-563 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] M.Mitsuo, T.Noguchi, Y.Nakajima, S.Aoki, X.Q.Ren, T.Sumizawa, M.Haraguchi, M.Kobayashi, M.Baba, Y.Nagata, S.Akiyama, T.Furukawa: "Binding site(s) on P-glycoprotein for a newlysynthesized photoaffinity analog of agosterol A."Oncology Research. 14. 39-48 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] T.Itoh, M.Kinoshita, S.Aoki, M.Kobayashi: "Komodoquinone A, a novel neuritogenic anthracycline, from marine Streptomyces sp.KS3."J Nat Prod.. 66. 1373-1377 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shunji Aoki et al.: "Pyridoacridine alkaloids inducing neuronal differentiation in a neuroblastoma cell line, from marine sponge Biemna fortis"Bioorg.Med.Chem.. 11. 1969-1973 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Xiao-Qin Ren, Shunji Aoki et al.: "Localization of the GSH-dependent photolabelling site of an agosterol A analog on human MRP1"Br J Pharmacol.. 138. 1553-1561 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shunji Aoki et al.: "In situ photoaffinity labeling of the target protein for lembehyne A, a neuronal differentiation inducer"FEBS Lett.. 544. 223-227 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] M.Mukai, Shunji Aoki et al.: "Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells"Cancer Sci.. 94. 557-563 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] M.Mitsuo, Shunji Aoki et al.: "Binding site(s) on P-glycoprotein for a newlysynthesized photoaffinity analog of agosterol A"Oncology Research. 14. 39-48 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Itoh, Shunji Aoki et al.: "Komodoquinone A, a novel neuritogenic anthracycline, from marine Streptomyces sp. KS3"J Nat Prod.. 66. 1373-1377 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shunji Aoki et al.: "Reversing Effect of Agosterol A, a Spongean Sterol Acetate, on Multidrug Resistance in Human Carcinoma Cells"Jpn. J. Cancer Res.. 92. 886-895 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shunji Aoki et al.: "Brianthein A, a novel briarane-type diterpene reversing multidrug resistance in human carcinoma cell line, from the gorgonian Briareum excavatum"Tetrahedron. 57. 8951-8957 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Zhe-Sheng Chen, Shunji Aoki et al.: "Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol a on MRP1 function"International Journal of Cancer. 93. 107-113 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Xiao-Qin Ren, Shunji Aoki et al.: "Glutathione (GSH) Dependent Binding of a Photoaffinity Analog of Agosterol A on the C-terminal Half of Human Multidrug Resistance Protein (MRP1)"J. Biol. Chem. 276. 23197-23206 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Xiao-Qin Ren, Shunji Aoki et al.: "A Positively Charged Amino Acid Proximate to the C-terminus of TM17 of MRP1 is Indispensable for GSH-dependent binding of Substrates and for Transport of LTC4"Biochemistry. 41. 14132-14140 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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