A novel mode of action of DNA alkylating anticancer agents

• Project/Area Number: 23510281
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical biology
• Research Institution: University of Shizuoka
• Principal Investigator: ASAI AKIRA 静岡県立大学, 薬学研究科(研究院), 教授 (60381737)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: がん / 抗がん剤 / DNAアルキル化剤 / 転写制御因子 / STAT3 / SH2 / 転写因子 / アルキル化剤

Research Abstract

Bendamustine (Benda) is an anti-lymphoma drug, which was recently approved in Japan. Although DNA has been believed to be primary target of this agent, the details of mechanism of action still remain unclear. We herein, for the first time, report STAT3 inhibition by Benda. The STAT3-SH2 antagonistic activity was shown by Benda but not by the inactive metabolites in the biochemical assay using recombinant human STAT3 protein. Furthermore, Benda suppressed both DNA-binding and transcriptional activity of STAT3 in the human breast cancer cell line MDA-MB-463. The competitive pull-down assay using the Benda analogs revealed that this agent tightly bound to cellular STAT3. Therefore, those results suggest that the previously reported anti-cancer and immunomodulation effects by this agent might be associated with its inhibitory effect on STAT3.

Research Products

• [Journal Article] Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line (2014)
  • Author(s): Ashizawa T, Akiyama Y, Miyata H, Iizuka A, Komiyama M, Kume A, Omiya M, Sugino T, Asai A, Hayashi N, Mitsuya K, Nakasu Y, Yamaguchi K
  • Journal Title: Int J Oncol. Volume: 411-8 Issue: 1 Pages: 411-418
  • DOI: 10.3892/ijo.2014.2439
  • Peer Reviewed
• [Journal Article] Novel multiplexed assay for identifying SH2 domain antagonists of STAT family proteins (2013)
  • Author(s): Takakuma K, Ogo N, Uehara Y, Takahashi S, Miyoshi N, Asai A
  • Journal Title: PLoS ONE Volume: 8
  • Peer Reviewed
• [Journal Article] Synthesis, structure.activity relationships and stereochemical investigations of new tricyclic pyridazinone derivatives as potential STAT3 inhibitors (2013)
  • Author(s): Masciocchi D, Gelain A, Porta F, Meneghetti F, Pedretti A, Celentano G, Barlocco D, Legnani L, Toma L, Kwon B, Asai A, Villa S
  • Journal Title: Med Chem Commun. Volume: 4 Pages: 1181-1188
  • Peer Reviewed
• [Journal Article] Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma (2013)
  • Author(s): Ashizawa T, Miyata H, Iizuka A, Komiyama M, Oshita C, Kume A, Nogami M, Yagoto M, Ito I, Oishi T, Watanabe R, Mitsuya K, Matsuno K, Furuya T, Okawara T, Otsuka M, Ogo N, Asai A, Nakasu Y, Yamaguchi K, Akiyama Y
  • Journal Title: Int J Oncol. Volume: 43 Pages: 219-217
  • Peer Reviewed
• [Journal Article] 創薬研究における点と線 (2013)
  • Author(s): 浅井章良、小郷尚久
  • Journal Title: ドラッグライクとドラッガブルの接点を探る細胞工学 Volume: 32 Pages: 644-648
• [Journal Article] Novel multiplexed assay for identifying SH2 domain antagonists of STAT family proteins (2013)
  • Author(s): 5) Takakuma K, Ogo N, Uehara Y, Takahashi S, Miyoshi N, Asai A
  • Journal Title: PLoS ONE Volume: 8 Issue: 8 Pages: e71646-e71646
  • DOI: 10.1371/journal.pone.0071646
  • Peer Reviewed
• [Journal Article] Synthesis, structure–activity relationships and stereochemical investigations of new tricyclic pyridazinone derivatives as potential STAT3 inhibitors (2013)
  • Author(s): 7) Masciocchi D, Gelain A, Porta F, Meneghetti F, Pedretti A, Celentano G, Barlocco D, Legnani L, Toma L, Kwon B, Asai A, Villa S.
  • Journal Title: Med Chem Commun Volume: 4 Issue: 8 Pages: 1181-1188
  • DOI: 10.1039/c3md00095h
  • Peer Reviewed
• [Journal Article] Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma (2013)
  • Author(s): Tadashi Ashizawa, Haruo Miyata, Akira Iizuka, Masaru Komiyama, Chie Oshita, Akiko Kume, Masahiro Nogami, Mika Yagoto, Ichiro Ito, Takuma Oishi, Reiko Watanabe, Koichi Mitsuya, Kenji Matsuno, Toshio Furuya, Tadashi Okawara, Masami Otsuka, Naohisa Ogo, Akira Asai, Yoko Nakasu, Ken Yamaguchi Yasuto Akiyama
  • Journal Title: International Journal of Oncology Volume: 43 Issue: 1 Pages: 219-227
  • DOI: 10.3892/ijo.2013.1916
  • Peer Reviewed
• [Journal Article] Biological and computational evaluation of an oxadiazole derivative (MD77) as a new lead for direct STAT3 inhibitors (2012)
  • Author(s): Masciocchi D, Villa S, Meneghetti F, Pedretti A, Barlocco D, Legnani L, Toma L, Kwon B, Nakano S, Asai A, Gelain A
  • Journal Title: Med Chem Commun. Volume: 3 Pages: 592-599
  • Peer Reviewed
• [Journal Article] Identification of novel kynurenine production-inhibiting benzenesulfonamide derivatives in cancer cells (2012)
  • Author(s): Nakano S, Takai K, Isaka Y, Takahashi S, Unno Y, Ogo N, Matsuno K, Takikawa O, Asai A
  • Journal Title: Biochem Biophys Res Commun Volume: 419 Pages: 556-561
  • Peer Reviewed
• [Journal Article] 創薬標的としての転写因子 STAT3 (2012)
  • Author(s): 浅井章良、松野研司
  • Journal Title: ファルマシア Volume: 48 Pages: 673-677
  • NAID: 110009901124
• [Journal Article] Biological and computational evaluation of an oxadiazole derivative (MD77) as a new lead for direct STAT3 inhibitors (2012)
  • Author(s): Daniela Masciocchi, Stefania Villa, Fiorella Meneghetti, Alessandro Pedretti, Daniela Barlocco, Laura Legnani, Lucio Toma, Byoung-Mog Kwon, Shintaro Nakano, Akira Asai, Arianna Gelain
  • Journal Title: Med. Chem. Commun Volume: 3 Issue: 5 Pages: 592-599
  • DOI: 10.1039/c2md20018j
  • Peer Reviewed
• [Presentation] STAT3転写活性に対するベンダムスチンの阻害作用 (2014)
  • Author(s): 岩本一徳、上原裕、海野雄加、小郷尚久、浅井章良
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 神経膠芽腫患者由来のがん性幹細胞の増殖に及ぼすSTAT3阻害剤STX-0119の効果 (2013)
  • Author(s): 芦澤忠、飯塚明、小宮山優、浅井章良、山口建、秋山靖人
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-04
• [Presentation] STATファミリー阻害剤探索のための新規マルチプレックスアッセイ系の開発 (2013)
  • Author(s): 髙熊万之、小郷尚久、上原裕、高橋進、三好奈央、浅井章良
  • Organizer: 日本ケミカルバイオロジー学会第8回年会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-20
• [Presentation] Platinum-based cancer chemotherapeutics inhibit STAT signaling by blocking the SH2 domain (2013)
  • Author(s): W. Joost Lesterhuis, Stanleyson V. Hat2, Carl G. Figdor, Susumu Takahashi, Cornelis J.A. Punt, Akira Asai, I. Jolanda M. De Vries
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Washington, DC
  • Year and Date: 2013-04-08
• [Presentation] STATファミリー阻害剤探索のための新規マルチプレックスアッセイ系の開発 (2013)
  • Author(s): 2. 髙熊万之、小郷尚久、上原裕、高橋進、三好奈央、浅井章良
  • Organizer: 日本ケミカルバイオロジー学会 第8回年会
  • Place of Presentation: 東京
• [Presentation] Identification of a novle STAT3 inhibitors structurally related to the oxadiazole derivative MD77 (2013)
  • Author(s): 5. Daniela Masciocchi, Stefania Villa, Federica Porta, Daniela Barlocco, Fiorella Meneghetti, Byoung-Mog Kwon, Akira Asai, Arianna Gelain
  • Organizer: XXII National Meeting on Medicinal Chemistry
  • Place of Presentation: ローマ
• [Presentation] PLATINUM-BASED CANCER CHEMOTHERAPEUTICS DIRECTLY INTERACT WITH STAT PROTEINS AND INHIBIT SIGNALING BY BLOCKING THE SH2 DOMAIN (2012)
  • Author(s): Stanleyson V. Hato, Carl G. Figdor, Susumu Takahashi, Anja E. Pen, Cornelis J.A. Punt, Akira Asai, I. Jolanda M. de Vries, W. Joost Lesterhuis
  • Organizer: 11th International Symposium on Platinum Coordination Compounds inCancer Chemotherapy
  • Place of Presentation: Verona
  • Year and Date: 2012-10-13
• [Presentation] MERGED STRUCTURES AS NEW STAT3 INHIBITORS: THE "CHIMERA" COMPOUNDS (2012)
  • Author(s): Arianna Gelain, Daniela Masciocchi, Stefania Villa, Fiorella Meneghetti, Alessandro Pedretti, Daniela Barlocco, Laura Legnani, Lucio Toma, Byoung-Mog Kwon, Shintaro Nakano, Akira Asai
  • Organizer: 22nd International Symposium on Medicinal Chemistry
  • Place of Presentation: Berlin
  • Year and Date: 2012-09-05
• [Presentation] New STAT3 inhibitors (2012)
  • Author(s): Arianna Gelain, Daniela Masciocchi, Stefania Villa, Fiorella Meneghetti, Alessandro1 Pedretti, Daniela Barlocco, Laura Legnani, Lucio Toma, Byoung-Mog Kwon, Shintaro Nakano, Akira Asai
  • Organizer: identification of a lead 21st National Meeting on Medicinal Chemistry
  • Place of Presentation: Palermo
  • Year and Date: 2012-07-18
• [Presentation] 静岡県における化合物ライブラリーシステムの構築 (2012)
  • Author(s): 小郷尚久、鈴木紳之、大場舞、小和田和宏、浅井章良
  • Organizer: 日本ケミカルバイオロジー学会第7回年会
  • Place of Presentation: 京都
  • Year and Date: 2012-06-08
• [Presentation] In silicoスクリーニングによるSTAT3阻害剤の探索 (2011)
  • Author(s): 増田吉昭、室谷歩、高橋理、横田川高峰、古谷利夫、松野研司、上原裕、大川原正、大塚雅巳、小郷尚久、芦澤忠、秋山靖人、 浅井章良
  • Organizer: 日本ケミカルバイオロジー学会第6回年会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-25
• [Presentation] Platinum-based cancer chemotherapeutics inhibit STAT signaling by blocking the SH2 domain
  • Author(s): W. Joost Lesterhuis, Stanleyson V. Hato, Carl G. Figdor, Susumu Takahashi, Cornelis J.A. Punt, Akira Asai, I. Jolanda M. De Vries
  • Organizer: American Association for Cancer Research Annual Meeting 2013
  • Place of Presentation: Washington, DC (USA)
• [Presentation] Platinum-based cancer chemotherapeutics directly interact with STAT proteins and inhibit signaling by blocking the SH2 domain
  • Author(s): Stanleyson V. Hato, Carl G. Figdor, Susumu Takahashi, Anja E. Pen, Cornelis J.A. Punt, Akira Asai, I. Jolanda M. de Vries, W. Joost Lesterhuis
  • Organizer: 11th International Symposium on Platinum Coordination Compounds in Cancer
  • Place of Presentation: Verona (Italy)
• [Presentation] Merged structures as new STAT3 inhibitors: the “chimera” compounds
  • Author(s): Arianna Gelain, Daniela Masciocchi, Stefania Villa, Fiorella Meneghetti, Alessandro Pedretti, Daniela Barlocco, Laura Legnani, Lucio Toma, Byoung-Mog Kwon, Shintaro Nakano, Akira Asai
  • Organizer: 22nd International Symposium on Medicinal Chemistry
  • Place of Presentation: Berlin (Germany)
• [Remarks] CURRENT RESEARCH PROJECTS
  • URL: http://w3pharm.u-shizuoka-ken.ac.jp/~tansaku/J%20Res.html