Analysis of a novel small-molecule compound inducing the degradation of a cisplatin resistance-related factor ERCC1

• Project/Area Number: 25640089
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kanazawa University
• Principal Investigator: MATSUNAGA Tsukasa 金沢大学, 薬学系, 教授 (60192340)
• Co-Investigator(Kenkyū-buntansha): INOBE Manabu 金沢大学, 薬学系, 准教授 (10312414) ; WAKASUGI Mitsuo 金沢大学, 薬学系, 助教 (80345595) ; NISHINAGA Mari 富山県衛生研究所, 研究員 (10646681)
• Co-Investigator(Renkei-kenkyūsha): KUNISHIMA Munetaka 金沢大学, 薬学系, 教授 (10214975) ; ODA Akifumi 金沢大学, 薬学系, 准教授 (50433511) ; ENDO Yoshio 金沢大学, がん進展制御研究所, 准教授 (30211783)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ヌクレオチド除去修復 / 阻害剤 / 抗癌剤 / シスプラチン / 低分子化合物 / 増感作用

Outline of Final Research Achievements

In this study, we have analyzed whether a small-molecule inhibitor of nucleotide excision repair (NERi) we recently found can potentiate the cytotoxic effects of cisplatin in cancer cells. The clonogenic survival assay revealed that NERi treatment increases the cisplatin-sensitivity of KKLS stomach cancer cell lines and A2780 ovarian cancer cell lines 2-3 fold. Using an immunoassay with damage-specific antibody, we showed that the removal of cisplatin-induced DNA intrastrand crosslinks is markedly attenuated by NERi treatment. Furthermore, in vivo experiments using murine Lewis lung carcinoma and C57BL/6 mice revealed that a combination of cisplatin and NERi significantly suppresses tumor growth, compared with cisplatin alone.

Research Products

• [Journal Article] Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells. (2014)
  • Author(s): Mitsuo Wakasugi, Takuma Sasaki, Megumi Matsumoto, Miyuki Nagaoka, Keiko Inoue, Manabu Inobe, Katsuyoshi Horibata, Kiyoji Tanaka, and Tsukasa Matsunaga
  • Journal Title: The Journal of biological chemistry Volume: 289 Pages: 28730-28737
  • DOI: 10.1074/jbc.m114.589747
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rapid proliferation of activated lymph node CD4+ T Cells is achieved by eliminating gap phases in cell cycle progression (2014)
  • Author(s): Mishima, T., Toda, S., Ando, Y., Matsunaga, T. and Inobe, M.
  • Journal Title: Cell. Mol. Biol. Lett. Volume: 19 Pages: 638-648
  • DOI: 10.2478/s11658-014-0219-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Concanavalin A-mediated T cell proliferation is regulated by Herpes Virus Entry Mediator costimulatory molecule (2014)
  • Author(s): Ando, Y., Yasuoka, C., Mishima, T., Ikematsu, T., Uede, T., Matsunaga, T. and Inobe, M.
  • Journal Title: In Vitro Cell. Dev. Biol. - Animal Volume: 50 Pages: 313-320
  • DOI: 10.1007/s11626-013-9705-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proteasome inhibitors and knockdown of SMG1 cause accumulation of Upf1 and Upf2 in human cells. (2014)
  • Author(s): Zhao, X., Nogawa, A., Matsunaga, T., Takegami, T., Nakagawa, H. and Ishigaki, Y.
  • Journal Title: Int. J. Oncol. Volume: 44 Pages: 222-228
  • DOI: 10.3892/ijo.2013.2149
  • Peer Reviewed
• [Journal Article] The scaffold protein JLP plays a key role in regulating ultraviolet B-induced apoptosis in mice. (2014)
  • Author(s): Enkhtuya R, Sato T, Wakasugi M, Tuvshintugs B, Miyata H, Sakurai T, Matsunaga T, Yoshioka K.
  • Journal Title: Genes Cells Volume: 19 Pages: 350-358
  • DOI: 10.1111/gtc.12135
  • Peer Reviewed
• [Presentation] DNA修復因子ERCC1-XPFの安定性と細胞内局在性を決定する要因の解析 (2015)
  • Author(s): 高森千枝、宮崎幸太郎、西永真理、大澤琢郎、若杉光生、松永 司
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 兵庫医療大学（神戸）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] NER-dependent DSB formation activates ATM signaling pathway in mammalian quiescent cells (2015)
  • Author(s): Wakasugi, M., Sasaki, T., Nagaoka, M., Matsumoto, M., Inoue, K., Horibata, K., Tanaka, K. and Matsunaga, T.
  • Organizer: Keystone Symposia “Genomic instability and DNA repair joint with DNA replication and recombination”
  • Place of Presentation: Whistler (Canada)
  • Year and Date: 2015-03-01 – 2015-03-06
• [Presentation] 生体内の様々な細胞におけるヌクレオチド除去修復に依存した二次的DNA損傷の生成 (2014)
  • Author(s): 若杉光生、長岡美由紀、堀田侑希、松永 司
  • Organizer: 日本放射線影響学会第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] シスプラチン抵抗性関連因子ERCC1を分解誘導する新規低分子化合物の同定 (2014)
  • Author(s): 松永 司、斎藤臣雄、長田裕之、遠藤良夫
  • Organizer: 第18回日本がん分子標的治療学会学術集会
  • Place of Presentation: TKPガーデンシティ仙台（仙台）
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] 新開発セルベースドアッセイ系を利用したヌクレオチド除去修復研究の新展開 (2013)
  • Author(s): 松永 司
  • Organizer: 日本環境変異原学会第42回大会・シンポジウム「光遺伝毒性」
  • Place of Presentation: 岡山コンベンションセンター
  • Invited
• [Presentation] 癌細胞のシスプラチン感受性を増感させるヌクレオチド除去修復阻害剤の作用機序 (2013)
  • Author(s): 松永 司、西永真理、長田裕之、若杉光生
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] ヌクレオチド除去修復を阻害する低分子化合物の作用機序に関する解析 (2013)
  • Author(s): 西永真理、宮崎幸太郎、福島直紀、高森千枝、若杉光生、斎藤臣雄、長田裕之、松永 司
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
• [Remarks] 松永研究室｜遺伝情報制御学
  • URL: http://www.p.kanazawa-u.ac.jp/~iden/