Radiosensitization of cancer stem-like cells that thrive under hypoxic conditions

• Project/Area Number: 16K10402
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Juntendo University
• Principal Investigator: Sasai Keisuke 順天堂大学, 医学部, 教授 (20225858)
• Co-Investigator(Kenkyū-buntansha): 田部 陽子 順天堂大学, 医学(系)研究科(研究院), 特任教授 (70306968)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 放射線増感 / 低酸素細胞 / がん幹細胞 / ヒートショックプロテイン / Sulfasalazine / グルタチオン / 低酸素放細胞射線増感 / sulfasalazine / 17-DMAG / Hsp90 / 癌幹細胞 / 低酸素環境 / DMAG / 放射線増感作用 / HIF1α / HSP90阻害剤

Outline of Final Research Achievements

Cancer stem-like cells are found in tumor niches and thrive under hypoxia. Hypoxic cells are radioresistant. This study tested the hypoxic cell radiosensitizing effects of sulfasalazine (SSZ) and 17-DMAG using a colony-formation assay and investigated their effects on protein expression, the cell cycle, and intracellular glutathione (GSH) concentrations. One mM SSZ significantly enhanced the radiosensitivity of hypoxic U251 MG and HSC-2 cells, but not normoxic cells. The treatment decreased intracellular GSH under both normoxia and hypoxia.
Treatment with 100 nM 17-DMAG for 24 h had weak or no radiosensitizing effects under normoxia, but significantly enhanced the radiosensitivity of both cell lines under hypoxia. 17-DMAG did not influence the cell cycle, but significantly increased the expression of Hsp70, a marker of Hsp90 inhibition, and inhibited the expression of HIF-1α.
SSZ and 17-DMAG are potential radiosensitizers, although the detailed mechanism requires further study.

Academic Significance and Societal Importance of the Research Achievements

腫瘍内の存在するがん幹細胞は治療抵抗性であり、がん治療後の再発原因と考えられている。とくに、がん幹細胞は低酸素ニッチェに存在するため、放射線感受性が低いと考えられる。本研究では、この放射線抵抗性を克服することを目的とした。
がん幹細胞に発現するCD44vにより安定化することで細胞内のGSH濃度を増加させるｘCTを潰瘍性大腸炎に長らく使用されてきたサルファサラジンが抑制することに注目して、本薬剤の低酸素細胞増感効果を明らかにした。サルファサラジンはこれまで臨床経験のある薬剤であり、臨床研究へつなげられる成果である。

Research Products

• [Presentation] Sulfasalazineによる低酸素放射線増感効果 (2020)
  • Author(s): 笹井啓資 齋藤香里 水野利恵 田部陽子
  • Organizer: 第 22回菅原・大西記念 癌治療増感シンポジウム 癌治療増感シンポジウム 癌治療増感シンポジウム 癌治療増感シンポジウム in 奈良
• [Presentation] Hypoxic radiosensitizing activity of sulfasalazine, a medicine to treat inflammatory bowel disease (2019)
  • Author(s): Sasai K, Mizuno R.
  • Organizer: 61st. Annual Meeting of American Society for Radiation Oncology
  • Int'l Joint Research
• [Presentation] 潰瘍性大腸炎治療薬Sulfasalazineによる低酸素細胞放射線増感効果 (2019)
  • Author(s): 水野利恵 笹井啓資
  • Organizer: 第21回癌治療増感研究シンポジウム
• [Presentation] Hypoxic radiosensitizing activity of Sulfasalazine, an inflammatory bowel disease medicine (2019)
  • Author(s): Keisuke Sasai, Rie Mizuno
  • Organizer: 61st Annual Meeting, the American Society for Radiation Oncology
  • Int'l Joint Research
• [Presentation] 低酸素細胞放射線増感に関する試み (2018)
  • Author(s): 水野利恵 笹井啓資
  • Organizer: 第20 回 菅原・大西記念 癌治療増感研究シンポジウムin 奈良
• [Presentation] Hypoxic radiosensitization by DMAG, an Hsp90 inhibitor (2017)
  • Author(s): Rie Mizuno, Mayumi Nakashiro, Keisuke Sasai
  • Organizer: 59th Annual Meeting of the American Society for Radiation Oncology
  • Int'l Joint Research