Regulation of human leukemic stem cell by reactive oxygen species (ROS) and its therapeutic applications in the clinics

• Project/Area Number: 19591137
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Saitama Medical University
• Principal Investigator: KIZAKI Masahiro Saitama Medical University, 医学部, 教授 (20161432)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 白血病 / 幹細胞 / 活性酸素 / 転写因子 / アポトーシス

Research Abstract

白血病の治療は抗癌剤による化学療法が主体であるが、時として致命的な合併症や副作用が問題となる。近年、白血病に対す分子標的療法が注目されているが、本研究においてはより侵襲の少ない新たな白血病に対する分子標的療法の確立を目的とした研究を展開した。緑茶成分EGCG は活性酸素(ROS)を産生し、ミエロペロキシダーゼ(MPO)を介して最終的にはDNA 障害活性の強いヒドロキシラジカルを産生することでヒト骨髄性白血病細胞のアポトーシスを誘導した。そこで、白血病の治癒を目的として、CD34 陽性CD38 陰性分画より、ヒト白血病幹細胞(LSC)を単離し、EGCG によるヒトLSC に対する効果を検討し、白血病に対する新たな分子標的療法確立のための基礎的な検討を行った。

Research Products

• [Journal Article] Cantharidine, a derivative of blister beatles, induces apoptosis in human multiple myeloma cells via inhibition of JAK/STAT pathway. (2008)
  • Author(s): Sagawa M, Nakazato T, Uchida H, Ikeda Y, Kizaki M
  • Journal Title: Cancer Sci. 99 Pages: 1820-1826
  • Peer Reviewed
• [Journal Article] New therapeutic approaches to acute myeloid leukemia (AML). (2008)
  • Author(s): Uchida H, Inokuchi K, Watanabe R, Tokuhira M, Kizaki M
  • Journal Title: Exp Opin Drug Dis. 3 Pages: 689-706
  • Peer Reviewed
• [Journal Article] New tubulin-polymerization inhibitor derived from thalidomide: implications for anti-myeloma effect. (2008)
  • Author(s): Kizaki M, Hashimoto Y
  • Journal Title: Curr Med Chem. 15 Pages: 754-765
  • Peer Reviewed
• [Journal Article] Biological significance of myeloperoxidase (MPO) on green teacomponent, EGCG-induced apoptosis: its therapeutic potential for myeloid leukemia. (2008)
  • Author(s): Kizaki M
  • Journal Title: Target Oncol. 3 Pages: 45-50
  • Peer Reviewed
• [Journal Article] Novel tubulin-polymerization inhibitor derived thalidomide directly induces apoptosis of human multiple myeloma cells: possible anti-myeloma mechanism of thalidomide. (2008)
  • Author(s): Iguchi T, Noguchi-Yachide T, Hashimoto Y, Nakazato T, Sagawa M, Ikeda Y, Kizaki M
  • Journal Title: Int J Mol Med. 21 Pages: 163-168
  • Peer Reviewed
• [Journal Article] Biological significance of myeloperoxidase (MPO) on green tea component, EGCG-induced apoptosis : its therapeutic potential for myeloid leukemia. (2008)
  • Author(s): Kizaki M
  • Journal Title: Targeted Oncology 3 Pages: 45-50
  • Peer Reviewed
• [Journal Article] New highly potent and specific E6 and E7 siRNAs for treatment of HPV16-positive cervical cancer. (2008)
  • Author(s): Yamato K, et al
  • Journal Title: Cancer Gene Therapy 15 Pages: 140-153
  • Peer Reviewed
• [Journal Article] New tubulin-polymerization inhibitor derived from thalidomide : implications for anti-myeloma effect. (2008)
  • Author(s): Kizaki M, et al
  • Journal Title: Current Medical Chemistry 15 Pages: 754-765
  • Peer Reviewed
• [Journal Article] New therapeutic approaches to acute myeloid leukemia (AML). (2008)
  • Author(s): Uchida H, et al
  • Journal Title: Expert Opinion on Drug Discovery 3 Pages: 689-706
  • Peer Reviewed
• [Journal Article] Cantharidin, a derivative of blister beatles, induces apoptosis in human multiple myeloma cells via inhibition of JAK/STAT pathway. (2008)
  • Author(s): Sagawa M, et al
  • Journal Title: Cancer Science 99 Pages: 1820-1826
  • Peer Reviewed
• [Journal Article] Structural development of benzhydrol-type l'-acetoxychavicol acetate (ACA) analogs as human leukemia cell-growth inhibitors based on QSAR analysis. (2008)
  • Author(s): Misawa T, et al
  • Journal Title: Chemical and Pharmaceutical Bulletin 56 Pages: 1490-1495
  • Peer Reviewed
• [Journal Article] Capsaicin inhibits the mitochondrial function of prohibitin 2 and induces apoptosis. (2008)
  • Author(s): Kuramori C, et al
  • Journal Title: Biochemical and Biophysical Research Communications 379 Pages: 519-525
  • Peer Reviewed
• [Journal Article] Novel tubulin-polymerization inhibitor derived thalidomide directly induces apoptosis of human multiple myeloma cells:possible anti-myeloma mechanism of thalidomide (2008)
  • Author(s): Iguchi T, et. al.
  • Journal Title: International Journal of Molecular Medicine 21 Pages: 163-168
  • Peer Reviewed
• [Journal Article] A natural peptide, dolastatin 15, induces G2/M cell cycle arrest and apoptosis in human multiple myeloma cells. (2007)
  • Author(s): Sato M, Sagawa M, Nakazato T, Ikeda Y, Kizaki M
  • Journal Title: Int J Oncol. 30 Pages: 1453-1459
  • Peer Reviewed
• [Journal Article] Myeloperoxidase is a key regulator of oxidative stress-mediated apoptosis of myeloid leukemia cells. (2007)
  • Author(s): Nakazato T, Sagawa M, Yamato K, Xian M, Yamato T, Suematsu M, Ikeda Y, Kizaki M
  • Journal Title: Clin Cancer Res. 13 Pages: 5436-5445
  • Peer Reviewed
• [Journal Article] Zoledronate induced S phase arrest accompanied by the DNA damage and the activation of ATM/Chk1/cdc25 pathway in human osteosarcoma cells. (2007)
  • Author(s): Iguchi T, Miyakawa Y, Saio K, Nakanishi M, Saya H, Ikeda Y, Kizaki M
  • Journal Title: Int J Oncol. 31 Pages: 285-291
  • Peer Reviewed
• [Journal Article] Zerumbone, a bioactive sesquterpene, induces G2/M cell cycle arrest and apoptosis of NB4 promyelocytic leukemic cells via a Fas/CD95- and mitochondria-mediated pathway. (2007)
  • Author(s): Xian M, Ito K, Nakazato T, Shimizu T, Chen C-K, Yamato K, Murakami A, Ohigashi H, Ikeda Y, Kizaki M
  • Journal Title: Cancer Sci. 98 Pages: 118-126
  • Peer Reviewed
• [Journal Article] Zerumbone,a bioactive sesquiterpene,induces G2/M cell cycle arrest and apoptosis of NB4 promvelocytic leukemic cells via a Fas/CD95-and mitochondria-mediated pathway (2007)
  • Author(s): Xian M, et. al.
  • Journal Title: Cancer Science 98 Pages: 118-126
  • Peer Reviewed
• [Journal Article] Zoledronate induced S phase arrest accompanied by the DNA damage and the activation of ATM/Chk1/cdc25 pathway in human osteosarcoma cells (2007)
  • Author(s): Iguchi T, et. al.
  • Journal Title: International Journal of Oncology 31 Pages: 285-291
  • Peer Reviewed
• [Journal Article] Myeloperoxidase is a key regulator of oxidative stress-mediated apoptosis of myeloid leukemic cells (2007)
  • Author(s): Nakazato T, et. al.
  • Journal Title: Clinical Cancer Research 13 Pages: 5436-5445
  • Peer Reviewed
• [Journal Article] Targeting NF-κB and induction of apoptosis by a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ),in Burkitt lymphoma cells (2007)
  • Author(s): Kimura N, et. al.
  • Journal Title: Leukemia Research 31 Pages: 1529-1535
  • Peer Reviewed
• [Journal Article] Emodin has a cytotoxic activity against human multiple myeloma as a Janus Kinase 2(JAK2)inhibitor (2007)
  • Author(s): Muto A, et. al.
  • Journal Title: Molecular Cancer Research 6 Pages: 987-994
  • Peer Reviewed
• [Journal Article] A natural peptide, dolastatin 15, induces G2/M cell cycle arrest and apoptosis in human multiple myeloma cells (2007)
  • Author(s): Sato M, et. al.
  • Journal Title: International Journal of Oncology 30 Pages: 1453-1459
  • Peer Reviewed
• [Presentation] 多発性骨髄腫に対する新たな分子標的療法の開発。腫瘍別シンポジウム3 造血器腫瘍における分子・細胞療法の開発 (2008)
  • Author(s): 木崎昌弘
  • Organizer: 第67 回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] 多発性骨髄腫に対する新たな分子標的療法の開発 (2008)
  • Author(s): 木崎 昌弘
  • Organizer: 第67回日本癌学会
  • Place of Presentation: 名古屋
• [Presentation] Gold compound auranofin induces apoptosis in myeloma cells via targeting IL-6 signaling pathway (2008)
  • Author(s): Nakaya A, et. al.
  • Organizer: 第12回ヨーロッパ血液学会
  • Place of Presentation: ウイーン、オーストリア
• [Presentation] A novel putative mechanism of anti-myloma activity targeted against heat shock protein 27 by derivative of artemisinin, artesnate. (2007)
  • Author(s): Chizuka A, Uchida H, Xian MJ, Shimizu T, Ikeda Y, Kizaki M
  • Organizer: 49th Annual Meeting of American Society of Hematolog.
  • Place of Presentation: 米国、Atlanta
• [Presentation] IL-6 シグナル伝達経路阻害による金製剤auranofin の多発性骨髄腫に対するアポトーシス誘導 (2007)
  • Author(s): 佐川森彦、中谷綾、仲里朝周、内田秀夫、武藤章弘、池田康夫、木崎昌弘
  • Organizer: 第69 回日本血液学会・第49 回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
• [Presentation] Gossypol induces apoptosis in myeloma cells by modulating phosphorylation of Bcl-2. (2007)
  • Author(s): Sadahira K, Sagawa M, Uchida H, Ikeda Y, and Kizaki M
  • Organizer: 第66 回日本癌学会
  • Place of Presentation: 横浜
• [Presentation] Oxidative stress-induced apoptosis in myeloid leukiemia: biological significance of myeloperoxidase (MPO) and its implications for prognosis. (2007)
  • Author(s): Kizaki M
  • Organizer: Korean Society of Hematology The Fourth AML/MDS Working Party Symposium.
  • Place of Presentation: Busan, Korea
• [Presentation] Oxidative stress-induced apoptosis in myeloid leukiemia:biological significance of myeloneroxidase(MPO)and its implications for prognosis (2007)
  • Author(s): Kizaki M
  • Organizer: 韓国血液学会 日韓ジョイントシンポジウム
  • Place of Presentation: プサン、韓国
• [Presentation] Gossypol induces apoptosis in myeloma cells by modulating phosphorylation of Bcl-2 (2007)
  • Author(s): Sadahira K, et. al.
  • Organizer: 第66回日本癌学会
  • Place of Presentation: 横浜
• [Presentation] IL-6シグナル伝達経路阻害による金製剤auranofinの多発性骨髄腫に対するアポトーシス誘導 (2007)
  • Author(s): 佐川 森彦, 他
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
• [Presentation] A novel putative mechanism of anti-myloma activity targeted against heat shock protein 27 by derivative of artemisimin, artesnate (2007)
  • Author(s): Chizuka A, et. al.
  • Organizer: 第49回米国血液学会
  • Place of Presentation: アトランタ、アメリカ合衆国
• [Book] 医療スタッフのための白血病ハンドブック (2009)
  • Author(s): 木崎昌弘(編集)
  • Total Pages: 236
  • Publisher: 中外医学社、東京
• [Book] 急性リンパ性白血病(今日の治療指針 2009 年版) (2009)
  • Author(s): 木崎昌弘(山口徹、北原光夫、福井次夫(総編集))
  • Publisher: 医学書院、東京
• [Book] 分子標的療法(分子細胞生物学辞典(第2版)) (2008)
  • Author(s): 木崎昌弘(村松正実(編集代表))
  • Total Pages: 803
  • Publisher: 東京化学同人、東京
• [Book] 今日の治療指針 (2008)
  • Author(s): 木崎 昌弘
  • Total Pages: 1753
  • Publisher: 医学書院
• [Book] 医療スタッフのための白血病ハンドブック (2008)
  • Author(s): 木崎 昌弘
  • Total Pages: 236
  • Publisher: 中外医学社
• [Book] 急性骨髄性白血病(今日の治療指針 2007 年版) (2007)
  • Author(s): 木崎昌弘(山口徹、北原光夫、福井次夫(総編集))
  • Publisher: 医学書院, 東京
• [Book] 造血器腫瘍の分類(カラーテキスト血液学) (2007)
  • Author(s): 木崎昌弘(押味和夫(編))
  • Publisher: 中外医学社、東京
• [Book] 急性白血病(カラーテキスト血液学) (2007)
  • Author(s): 木崎昌弘(押味和夫(編))
  • Publisher: 中外医学社、東京
• [Book] カラーテキスト血液学 (2007)
  • Author(s): 木崎 昌弘
  • Publisher: 中外医学社
• [Book] 今日の治療指針2007年版 (2007)
  • Author(s): 木崎 昌弘
  • Publisher: 医学書院