Exploring the mechanism of a mitochondria redox-mediated chemical enhancement of cell death induced by radiation and hyperthermia, and its application for cancer therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07614
• 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 Qing-Li 富山大学, 学術研究部医学系, 助教 (90313593)
• Co-Investigator(Kenkyū-buntansha): 小川 良平 富山大学, 学術研究部医学系, 准教授 (60334736) ; 崔 正国 福井大学, 学術研究院医学系部門, 講師 (90572115)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 温熱 / 細胞死

Outline of Final Research Achievements

Hyperthermia (HT) alone often falls short in inducing substantial cancer cell death. Here, we unveil Mito-Tempo as a potent thermosensitizer that amplifies cell death in human cervical cancer (HeLa cells). Co-treatment with MT (0.4 mM) and HT (42°C) significantly increased apoptosis. This combination heightened intracellular reactive oxygen species (ROS) generation while reducing mitochondrial membrane potential, culminating in elevated Bax expression and decreased Mcl-1, activating caspase-3. Concurrently, we observed autophagy alterations, marked by increased LC3-II and p62 expression. The combination inhibited autophagic flux and lysosomal function, evidenced by reduced LAMP-1 and Cathepsin D, and increased lysosomal pH. Notably, the apoptosis intensification with an autophagy inhibitor (Chloroquine; CQ) underscores the significance of autophagy disruption in this process. MT enhances HT-induced apoptosis in HeLa cells, implicating autophagy flux disruption as a key mechanism.

Free Research Field

放射線医学

Academic Significance and Societal Importance of the Research Achievements

放射線、ハイパーサーミア癌治療においては、高精度照射技術が進み治療効果が向上しているが、治療抵抗性細胞（低酸素性細胞や癌幹細胞）の存在が新たな課題である。ミトコンドリアを標的とするニトロキシドであるMito-Tempoは温熱による細胞死増感の分子機構を解明することによる癌治療抵抗性機構の抑制および癌治療の成績を高めることができる。新たな癌治療法および癌治療薬開発への貢献が期待できる。