Overcoming the drug resistance of cancer stem cells by targeting JNK pathway

• Project/Area Number: 15K18437
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Yamagata University
• Principal Investigator: Suzuki Shuhei 山形大学, 医学部, 助教 (90637175)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 癌 / 化学療法 / JNK / 活性酸素種 / 薬剤抵抗性 / xenograft / 癌幹細胞 / 薬剤感受性

Outline of Final Research Achievements

In this study, we revealed that JNK inhibition amplifies chemotherapy-induced reactive oxygen species leading chemo-sensitivity in intractable cancer stem cells(CSCs) such as lung cancer CSCs and glioblastoma CSCs as well as pancreas cancer CSCs through attenuation of the scavenging process, by catalase and MnSOD in particular. Particular scavenging substance such as BHT is able to cancel amplifying chemotherapy-induced reactive oxygen species and chemo-sensitivity. We also succeeded to establish in vivo therapeutic model with xenograft. In addition to common JNK inhibitor SP600125, AS602801 clinically is proven to also obtain the same effect, and we discovered drug-X which inhibits JNK.
We reported some presentation in an academic congress and in publication. And the remains are under preparation to be submitted to the academic journals.

Research Products

• [Journal Article] Time-staggered inhibition of JNK effectively sensitizes chemoresistant ovarian cancer cells to cisplatin and paclitaxel (2016)
  • Author(s): Seino M, Okada M, Sakaki H, Takeda H, Watarai H, Suzuki S, Seino S, Kuramoto K, Ohta T, Nagase S, Kurachi H, Kitanaka C
  • Journal Title: Oncology Reports Volume: 35 Issue: 1 Pages: 593-601
  • DOI: 10.3892/or.2015.4377
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo. (2016)
  • Author(s): Okada M, Kuramoto K, Takeda H, Watarai H, Sakaki H, Seino S, Seino M, Suzuki S, Kitanaka C.
  • Journal Title: Oncotarget Volume: 19 Issue: 19 Pages: 27021-27032
  • DOI: 10.18632/oncotarget.8395
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Aripiprazole, an Antipsychotic and Partial Dopamine Agonist, Inhibits Cancer Stem Cells and Reverses Chemoresistance. (2016)
  • Author(s): Suzuki S, Okada M, Kuramoto K, Takeda H, Sakaki H, Watarai H, Sanomachi T, Seino S, Yoshioka T, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 10 Pages: 5153-5161
  • Peer Reviewed
• [Journal Article] Impact of H3K27 Demethylase Inhibitor GSKJ4 on NSCLC Cells Alone and in Combination with Metformin. (2016)
  • Author(s): Watarai H, Okada M, Kuramoto K, Takeda H, Sakaki H, Suzuki S, Seino S, Oizumi H, Sadahiro M, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 11 Pages: 6083-6092
  • Peer Reviewed
• [Journal Article] Rho-Associated Protein Kinase (ROCK) Inhibitors Inhibit Survivin Expression and Sensitize Pancreatic Cancer Stem Cells to Gemcitabine. (2016)
  • Author(s): Takeda H, Okada M, Suzuki S, Kuramoto K, Sakaki H, Watarai H, Sanomachi T, Seino S, Yoshioka T, Kitanaka C.
  • Journal Title: Anticancer Res. Volume: 12 Pages: 6311-6318
  • Peer Reviewed
• [Journal Article] GSKJ4, A Selective Jumonji H3K27 Demethylase Inhibitor, Effectively Targets Ovarian Cancer Stem Cells. (2015)
  • Author(s): Sakaki H, Okada M, Kuramoto K, Takeda H, Watarai H, Suzuki S, Seino S, Seino M, Ohta T, Nagase
  • Journal Title: Anticancer Res. Volume: 35 Pages: 6607-6614
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 膵癌幹細胞がもつ薬剤耐性へのＪＮＫの関与. (2015)
  • Author(s): 鈴木修平,吉岡孝志
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山全日空ホテル（愛媛県松山市）
  • Year and Date: 2015-06-11
• [Book] 月刊「細胞」 (2017)
  • Author(s): 鈴木修平, 吉岡孝志, 岡田雅司.
  • Total Pages: 156
  • Publisher: 北隆館／ニュー・サイエンス社