New approach of cancer research; mitochondrial respiratory chain inhibitors as a new therapeutic target.

• Project/Area Number: 25450442
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: The University of Tokyo
• Principal Investigator: Nakagawa Takayuki 東京大学, 農学生命科学研究科, 准教授 (40447363)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 犬乳腺癌 / ミトコンドリア呼吸鎖 / AMPK / メトホルミン / ニコチンアミドアデニンジヌクレオチド / ミトコンドリア呼吸鎖複合体阻害薬 / 犬乳腺腫瘍 / ニコチンアミドアデニンヌクレオチド

Outline of Final Research Achievements

The multi-drug screening showed the high sensitivity of a malignant clone of canine mammary gland tumor (cMGT) cell line, CHMp-5b to mitochondrial respiratory chain inhibitors (MRCIs). While Metformin, one of the MRCIs, exhibited its anti-tumor effect through AMPK pathway on low sensitive clonal cell line, CHMp-13a, it induced G0/G1 cell cycle arrest in AMPK-independent manner on CHMp-5b. Cellular nicotinamide adenine dinucleotide (NAD) amount was decreased by metformin which exerted anti-proliferative effect, though the ATP amount was not changed. These results highlighted potential of metformin as a novel treatment for cMGT as well as a novel NAD-dependent mechanism.

Research Products

• [Journal Article] Anti-tumour effect of metformin in canine mammary gland tumour cells (2015)
  • Author(s): Saeki, K., Watanabe, M., Michishita, M., Tsuboi, M., Sugano, S., Yoshitake, R., Murai, K., Tanaka, Y., Ong, S.M., Saito, T., Matsumoto, K., Fujita, N., Nishimura, R., Nakagawa, T.
  • Journal Title: The Veterinary Journal Volume: 205 Issue: 2 Pages: 297-304
  • DOI: 10.1016/j.tvjl.2015.04.026
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phenotypic screening of a library of compounds against metastatic and non-metastatic clones of a canine mammary gland tumour cell line (2015)
  • Author(s): Saeki, K., Watanabe, M., Tsuboi, M., Sugano, S., Yoshitake, R., Tanaka, Y., Ong, S.M., Saito, T., Matsumoto, K., Fujita, N., Nishimura, R., Nakagawa, T.
  • Journal Title: The Veterinary Journal Volume: 205 Issue: 2 Pages: 288-296
  • DOI: 10.1016/j.tvjl.2015.04.025
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Metformin-induced growth inhibition of a canine mammary gland tumor cell line was partially attenuated by external compensation of nicotinamide adenine dinucleotide. (2015)
  • Author(s): Saeki, K., Fujita, N., Nishimura, R., Nakagawa, T.
  • Organizer: 第15回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学（東京都・文京区）
  • Year and Date: 2015-06-27
• [Presentation] External compensation of nicotinamide adenine dinucleotide partly attenuated metformin-induced growth inhibition of canine mammary gland tumor cell line. (2014)
  • Author(s): Saeki K, Fujita N, Nishimura R, Nakagawa T.
  • Organizer: 4th Conference of Asian Society of Veterinary Surgery(AiSVS)
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-12-06 – 2014-12-07
• [Presentation] Metformin exerts anti-proliferative effect through both AMPK-dependent and independent mechanism on canine mammary gland tumor (CMGT) cells. (2014)
  • Author(s): Saeki K, Watanabe M, Tsuboi M, Sugano S, Yoshitake R, Tanaka Y, Ong SM, Saito T, Matsumoto K, Fujita N, Nishimura R, Nakagawa T.
  • Organizer: Veterinary Cancer Society annual meeting 2014
  • Place of Presentation: St. Louis, United States
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] The anti-tumor effect of metformin on canine mammary tumor cells. (2014)
  • Author(s): Saeki K, Watanabe M, Nishimura R, Nakagawa T.
  • Organizer: 東京大学第14回生命科学シンポジウム
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2014-04-26
• [Presentation] ミトコンドリア呼吸鎖阻害薬の犬悪性乳腺腫瘍細胞に対する抗腫瘍効果に関する検討
  • Author(s): 佐伯亘平、山本博紀、田中由依子、花房明生、翁秀敏、松本香織、斎藤友睦、ナンチイスニラチョン、西村亮平、中川貴之
  • Organizer: 第156回日本獣医学会学術集会
  • Place of Presentation: 岐阜大学（岐阜県岐阜市）
• [Presentation] ANTI-DIABETIC DRUG METFORMIN INHIBITS PROLIFERATION OF CANINE MAMMARY GLAND TUMOR (CMGT) CELL LINES IN VITRO AND IN XENOGRAFT MOUSE MODEL
  • Author(s): Kohei Saeki, Hiroki Yamamoto, Yuiko Tanaka, Mimu Hanafusa, Ryohei Nishimura and Takayuki Nakagawa
  • Organizer: Veterinary Cancer Society 2013 annual conference
  • Place of Presentation: Minneapolis Marriott City Center, Minneapolis, MN, USA