Overcomingtherapy resistanceofintractable cancersviamodulation of mitochondrial energy metabolism

2011 Fiscal Year Final Research Report

• Project/Area Number: 22650235
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Clinical oncology
• Research Institution: Yamagata University
• Principal Investigator: SEINO Shizuka 山形大学, 医学部, 助手 (80571653)
• Co-Investigator(Renkei-kenkyūsha): KITANAKA Chifumi 山形大学, 医学部, 教授 (70260320) ; TOMIYAMA Arata 山形大学, 医学部, 助教 (40385810)
• Project Period (FY): 2010 – 2011
• Keywords: 抗がん物質探索 / ケミカルバイオロジー

Research Abstract

In this study, we aimed at overcoming the therapeutic resistance of intractable cancersthrough activation of mitochondrial respiration. In the course of the study, we identified achemical agent capable of promoting mitochondrial respiration of glioma cells and alsoconfirmed that the chemical agent overcomes temozolomide resistance of glioma cells invitro. In vivo, the chemical agent synergized with temozolomide to inhibit tumor growth inthe subcutaneous xenograft model. However, the synergistic anti-tumor effect of thesedrugs remains to be demonstrated in the intracranial xenograft model.

Research Products

• [Journal Article] Targeting JNK for therapeutic depletion of stem-like glioblastoma cells (2012)
  • Author(s): Matsuda K, Sato A, Okada M, Shibuya K, Seino S, Suzuki K, Watanabe E, Narita Y, Shibui S, Kayama T, Kitanaka C
  • Journal Title: Sci Rep Volume: 2 Pages: 516
  • DOI: doi:10.1038/srep00516.
  • Peer Reviewed
• [Journal Article] Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK (2012)
  • Author(s): Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, Suzuki K, Narita Y, Shibui S, Kayama T, Kitanaka C
  • Journal Title: Stem Cells Transl Med Volume: 1 Pages: 811-824
  • Peer Reviewed
• [Journal Article] MEK-ERK signaling dictates DNA-repair gene MGMT expression and temozolomide resistance of stem-like glioblastoma cells via the MDM2-p53 axis (2011)
  • Author(s): Sato A, Sunayama J, Matsuda K, Seino S, Suzuki K, Watanabe E, Tachibana K, Tomiyama A, Kayama T, Kitanaka C
  • Journal Title: StemCells Volume: 29 Pages: 1942-1951
  • Peer Reviewed
• [Journal Article] FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity (2011)
  • Author(s): Sunayama J, Sato A, Matsuda KI, Tachibana K, Watanabe E, Seino S, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C
  • Journal Title: Stem Cells Volume: 29 Pages: 1327-1337
  • Peer Reviewed
• [Journal Article] MEK-ERK-dependent multiple caspase activation via mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death (2010)
  • Author(s): Tomiyama A, Tachibana K, Suzuki K, Seino S, Sunayama J, Matsuda KI, Sato A, Matsumoto Y, Nomiya T, Nemoto K, Yamashita H, Kayama T, Ando K, Kitanaka C
  • Journal Title: Cell Death Dis Volume: 1 Pages: e60
  • DOI: doi:10.1038/cddis.2010.37.
  • Peer Reviewed
• [Presentation] グリオーマ幹細胞における FoxO3aを介した分化と造腫瘍能の制御 (2011)
  • Author(s): 佐藤篤,砂山潤,松田憲一朗,立花研,渡部江梨子,清野静香,鈴木香,成田善孝,渋井壮一郎,富山新太,北中千史,嘉山孝正
  • Organizer: 第29回日本脳腫瘍学会学術総会
  • Place of Presentation: 下呂(水明館)
  • Year and Date: 2011-11-27
• [Presentation] グリオーマ幹細胞におけるMGMT発現制御の分子機構に関する検討 (2011)
  • Author(s): 佐藤篤,松田憲一朗,砂山潤,清野静香,鈴木香,渡部江梨子,立花研,富山新太,北中千史,嘉山孝正
  • Organizer: 第12回日本分子脳神経外科学会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2011-10-15
• [Presentation] MEK経路阻害によるMGMT発現およびテモゾロミド感受性に関する検討 (2011)
  • Author(s): 佐藤篤,松田憲一朗,砂山潤,清野静香,鈴木香,櫻田香,立花研,富山新太,北中千史,嘉山孝正
  • Organizer: 第70回日本脳神経外科学会総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2011-10-12
• [Presentation] グリオーマ幹細胞におけるMGMT発現とテモゾロミド感受性に関する検討 (2010)
  • Author(s): 佐藤篤,松田憲一朗,砂山潤,清野静香,鈴木香,櫻田香,立花研,富山新太,北中千史,嘉山孝正
  • Organizer: 第28回日本脳腫瘍学会
  • Place of Presentation: 軽井沢(軽井沢プリンスホテル)
  • Year and Date: 2010-11-28