Induction of distinct cell death types and sensitization to radiation by using chemical stressors

• Project/Area Number: 18K07708
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: University of Toyama
• Principal Investigator: ZHAO QINGLI 富山大学, 学術研究部医学系, 助教 (90313593)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 温熱 / ROS / 細胞死 / 放射線 / Cell death / Radiation

Outline of Final Research Achievements

In this study, we determined that Tempo combine treatment with hyperthermia rapidly induced autophagic cell death in HeLa cells. 5 mM Tempo-44℃/20 min combination induced apoptosis, while 5 mM Tempo-44℃/60 min combination induced autophagic cell death in HeLa cells. This co-treatment inhibited the processing of heat-activated procaspase-3 into active small subunits, leading to the inhibition of caspase-dependent apoptosis, and results in the induction of autophagic cell death. Furthermore, the gene chip analysis showed the up-regulation of TP53INP1 gene in the combination treatment. Subsequently, the combination of Mito-Tempo and 44℃/60 min induced cell death in a dose-dependent manner. Mito-Tempo induced approximately 10-fold higher cell death than Tempo. Thus, the Mito-Tempo is a unique thermo-sensitizer which synergistically induce more apoptotic and autophagic cell death.

Academic Significance and Societal Importance of the Research Achievements

最近の研究で細胞死は極めて多様であること、細胞死の様式変換が癌治療成績に関係することが判明してきており、本研究により、全体のメカニズムの一端が分子水準で明らかになった。使用する薬剤の臨床使用可能性が判るとともに、細胞死の様式変換に関わる新たな薬剤開発に繋がる研究情報が得られる。研究結果からこのメカニズムの解明は癌の治療および治療薬の開発に寄与すると思われる。

Research Products

• [Journal Article] A New Ciprofloxacin-derivative Inhibits Proliferation and Suppresses the Migration Ability of HeLa Cells (2021)
  • Author(s): FATHY MOUSTAFA、SUN SIJIA、ZHAO QING-LI、ABDEL-AZIZ MOHAMED、ABUO-RAHMA GAMAL EL-DIN A.、AWALE SURESH、NIKAIDO TOSHIO
  • Journal Title: Anticancer Research Volume: 40 Issue: 9 Pages: 5025-5033
  • DOI: 10.21873/anticanres.14505
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Modulation of Apoptosis and Epithelial-Mesenchymal Transition E-cadherin/TGF-beta/Snail/TWIST Pathways by a New Ciprofloxacin Chalcone in Breast Cancer Cells (2021)
  • Author(s): Rania Alaaeldin, Gamal El-Din A Abuo-Rahma, Qing-Li Zhao, Moustafa Fathy
  • Journal Title: Anticancer Research Volume: 41 Issue: 5 Pages: 2383-2395
  • DOI: 10.21873/anticanres.15013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-psychotic drugs scavenge radiation-induced hydroxyl radicals and intracellular ROS formation, and protect apoptosis in human lymphoma U937 cells (2019)
  • Author(s): Zhao QL, Ito H, Kondo T, Uehara T, Ikeda M, Abe H, Saitoh JI, Noguchi K, Suzuki M, Kurachi M
  • Journal Title: Free Radic Res Volume: 53 Issue: 3 Pages: 304-312
  • DOI: 10.1080/10715762.2019.1572889
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antipsychotic drugs scavenge radiation-induced hydroxyl radicals and intracellular ROS formation, and protect apoptosis in human lymphoma U937 cells (2019)
  • Author(s): Zhao, Q-L. Ito, H. Kondo, T. Uehara, T. Ikeda, M. Abe, H. Saitoh, J-I. Noguchi, K. Suzuki, M. Kurachi, M.
  • Journal Title: Free Radical Research Volume: 53 Pages: 304-312
• [Presentation] Tempo induces switch between apoptosis and autophagy in combination with hyperthermia via modulation of TP53INP1 gene (2019)
  • Author(s): Zhao Q-L., Rehman M. U., Kondo T., Ogawa R., Saitoh J-I., Noguchi K.
  • Organizer: SfRBM 2019 annual conference
  • Int'l Joint Research