Hypoxic radiosensitization by DMAG, an Hsp90 inhibitor

Research Project

Project/Area Number	25461927
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)
Research Collaborator	ASAHINA Taito
Project Period (FY)	2013-04-01 – 2017-03-31
Project Status	Completed (Fiscal Year 2016)
Budget Amount *help	¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000) Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000) Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords	低酸素細胞放射線増感 / Hｓｐ90阻害剤 / DMAG / Hsp90阻害剤 / 低酸素細胞 / 放射線増感 / Hsp90 / 低酸素 / 17-DMAG / heat-shock protein 90 / 低酸素環境
Outline of Final Research Achievements	We investigated the radiosensitizing activity of 17-[2-(dimethylamino)ethyl]amino-17-desmethoxygeldanamycin (DMAG), an inhibitor of Hsp90, on hypoxic cells.　Two human tumor cell lines, HT1080 and HeLa, were used. The radiosensitivity of cells was assessed by a standard colony-forming assay. The exposure of HeLa cells to 100nM DMAG for 24 h significantly increased the expression of Hsp70, a marker of Hsp90 inhibition. However, there was no difference in its expression between cases with and without hypoxic treatment for 4 h. Exposure to DMAG for 24 h was slightly cytotoxic, but no further effect was observed with the additional hypoxic treatment. DMAG at 100nM showed a weak radiosensitizing effect on both cells under oxic conditions.However, Sensitizer enhancement ratios for hypoxic HeLa and HT1080 cells were significantly greater than those for oxic cells. Western blot analysis also demonstrated that the treatment decreased the expression of HIF-1 alpha.