Fundamental research for developing new therapeutic approach of multiple myeloma targeting its progenitor cells by reactive oxygen species (ROS)

• Project/Area Number: 15K09490
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Saitama Medical University
• Principal Investigator: Kizaki Masahiro 埼玉医科大学, 医学部, 教授 (20161432)
• Co-Investigator(Renkei-kenkyūsha): OKUDA AKIHIKO 埼玉医科大学, 医学部, 教授 (60201993)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 多発性骨髄腫 / 前駆細胞 / 活性酸素 / 細胞死 / 細胞周期 / NF-κB / DNA修復 / プロテアソーム / シグナル伝達機構 / Wnt/β-catenin

Outline of Final Research Achievements

Multiple myeloma is one of the refractory hematological malignant disorder. It has reported that NF-κB signaling is important for the regulation of proliferation of myeloma cells and their stem/progenitor cells. In the present study, it has shown that the sensitivity of reactive oxygen species (ROS) in myeloma cells and their progenitor cells is higher than that of other hematological malignancies. New NF-κB inhibitor TM-233 was inhibited proliferation and induced cell death of myeloma cells and their progenitor cells via production of ROS in dose- and time-dependent manner. In addition, cell cycle checkpoint kinase WEE-1 inhibitor MK-1775 was also induced cell death of these cells via DNA repair process. From these results, new NF-κB inhibitor TM-233 and WEE-1 inhibitor MK-1775 might be possible novel therapeutic agents for the treatment of multiple myeloma.

Research Products

• [Journal Article] Ribonucleotide Reductase Catalytic Subunit M1 (RRM1) as a Novel Therapeutic Target in Multiple Myeloma. (2017)
  • Author(s): Sagawa M, Ohguchi H, Harada T, Samur MK, Tai YT, Munshi NC, Kizaki M, Hideshima T, Anderson KC.
  • Journal Title: Clinical Cancer Research Volume: 23 Issue: 17 Pages: 5225-5237
  • DOI: 10.1158/1078-0432.ccr-17-0263
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Role of Intracellular Signaling Pathways in the Pathogenesis of Multiple Myeloma and Novel Therapeutic Approaches (2016)
  • Author(s): Kizaki M, Tabayashi T
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 56 Issue: 1 Pages: 20-27
  • DOI: 10.3960/jslrt.56.20
  • NAID: 130005158798
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lipopolisaccharide-induced CXCL10 mRNA and six stimulant-mRNA combinations in whole blood: Novel biomarkers for bortezomib responses obtained from a prospective multicenter observation trial for patients with multiple myeloma. (2015)
  • Author(s): Watanabe T, Mitsuhashi M, Sagawa M, Ri M, Suzuki K, Abe M, Ohmachi K, Nakagawa Y, Nakamura S, Chosa M, Iida, Kizaki M
  • Journal Title: PLoS One Volume: 10 (6) Issue: 6 Pages: e0128662-e0128662
  • DOI: 10.1371/journal.pone.0128662
  • Peer Reviewed / Open Access
• [Journal Article] TM-233, a novel analog of 1'-acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities. (2015)
  • Author(s): Sagawa M, Tabayashi T, Kimura Y, Tomikawa T, Nemoto-Anan T, Watanabe R, Tokuhira M, Ri M, Hashimoto Y, Iida S, Kizaki M.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 4 Pages: 438-446
  • DOI: 10.1111/cas.12616
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Structure-Activity Relationships of Benzhydrol Derivatives Based on 1'-Acetoxychavicol Acetate (ACA) and their Inhibitory Activities on Multiple Myeloma Cell Growth via Inactivation of the NF-kB Pathway (2015)
  • Author(s): Takashi Misawa, Kosuke Dodo, Minoru Ishikawa, Yuichi Hashimoto, Morihiko Sagawa, Masahiro Kizaki, Hiroshi Aoyama
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 23 Issue: 9 Pages: 2241-2246
  • DOI: 10.1016/j.bmc.2015.02.039
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 分子標的療法：ビタミンから創薬へ (2017)
  • Author(s): 木崎昌弘
  • Organizer: 第79回日本血液学会学術集会
  • Invited
• [Presentation] 多発性骨髄腫におけるRibonucleotide reductase large subunit (RRM1)の新規治療標的としての有用性 (2017)
  • Author(s): 佐川森彦、大口裕人、原田武志、Samur MK、Tai Y-Z、Munshi NC, 木崎昌弘、秀島輝、Anderson KC
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 細胞周期チェックポイントキナーゼを標的とした多発性骨髄腫に対する新しい治療 (2017)
  • Author(s): 多林孝之、田中佑加、高橋康之、富川武樹、佐川森彦、阿南朋恵、渡部玲子、得平道英、木崎昌弘
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Inhibition of WEE1 induces cell death of both bortezomib- and lenalidomide-resistant multiple myeloma cells: a novel therapeutic approach targeting cell-cycle checkpoint kinase. (2016)
  • Author(s): Tabayashi T, Tanaka Y, Takahashi Y, Kimura Y, Tomikawa T, Sagawa M, Anan-Nemoto T, Watanabe R, Tokuhira M, Kizaki M
  • Organizer: 58th Annual Meeting of American Society of Hematology
  • Place of Presentation: San Diego（アメリカ合衆国）
  • Year and Date: 2016-12-03
• [Presentation] The efficacy and safety of weekly bortezomib containing VMP followed by bortezomib maintenance therapy in unfit or frail multiple myeloma patients. (2016)
  • Author(s): Takezako N, Tokuhira M, Sekiguchi N, Kurihara Y, Ito K, Kurimoto M, Suzuki K, Kizaki M
  • Organizer: 58th Annual Meeting of American Society of Hematology
  • Place of Presentation: San Diego（アメリカ合衆国）
  • Year and Date: 2016-12-03
• [Presentation] Novel therapy for both bortezomib- and lenalidomide-resistant multiple myeloma targeting TOPK. (2016)
  • Author(s): 高橋康之、多林孝之、田中佑加、木村勇太、富川武樹、佐川森彦、阿南朋恵、渡部玲子、得平道英、木崎昌弘
  • Organizer: 第78回日本血液学会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-10-13
• [Presentation] 分子病態に基づく造血器腫瘍の診断と治療 (2016)
  • Author(s): 木崎昌弘
  • Organizer: 第17回日本検査血液学会
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2016-08-06
  • Invited
• [Presentation] 造血器腫瘍における治療の進歩：ビタミンから分子標的治療薬へ (2016)
  • Author(s): 木崎昌弘
  • Organizer: 第14回日本臨床腫瘍学会
  • Place of Presentation: 神戸国際展示場・会議場（神戸）
  • Year and Date: 2016-07-28
  • Invited
• [Presentation] Novel Therapeutic approach to overcome both bortezomib and lenalidomide resistant multiple myeloma by targeting TOPK/PBK. (2015)
  • Author(s): Tabayashi T, Takahashi T, Kimura Y, Tomikawa T, Nemoto Anan T, Watanabe R, Tokuhira M, Mori S, Kizaki M
  • Organizer: 57th Annual Meeting of American Society of Hematology
  • Place of Presentation: オーランド（アメリカ合衆国）
  • Year and Date: 2015-12-05
• [Presentation] 新規NF-κB阻害剤TM-233による骨髄腫細胞におけるボルテゾミブ耐性の克服 (2015)
  • Author(s): 多林孝之、佐川森彦、富川武樹、高橋康之、木村勇太、阿南朋恵、渡部玲子、得平道英、李政樹、飯田真介、木崎昌弘
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: ホテル金沢（石川県・金沢市）
  • Year and Date: 2015-10-16
• [Presentation] TM-233, a novel analog of ACA, induces cell death in multiple myeloma cells by targeting JAK/STAT and proteasome dual pathways. (2015)
  • Author(s): Kizaki M, Tabayashi T, Sagawa M, Tomikawa T, Tokuhira M, Iida S, Li M, Hashimoto Y
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-10-09