title: TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation.
abstract: Hsp90 inhibitors have been investigated as cancer therapeutics in monotherapy and to augment radiotherapy; however, serious adverse effects of early-generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here, we investigated the radiosensitizing effects of TAS-116 in low linear energy transfer (LET) X-ray and high LET carbon ion-irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of noncancerous human fibroblasts. TAS-116 increased the number of radiation-induced γ-H2AX foci and delayed the repair of DNA double-strand breaks (DSB). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and nonhomologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell-cycle progression marker, markedly increasing G2-M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared with either individual treatment. These results demonstrate that TAS-116 radiosensitizes human cancer cells to both X-rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell-cycle arrest. The promising results of combination TAS-116 + carbon ion radiotherapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation. Mol Cancer Ther; 16(1); 16-24. ©2016 AACR.
authors.affiliation: Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Younghyun
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.|Department of Nuclear Engineering and Management, School of Engineering, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Sunada
authors.affiliation: Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirakawa
authors.affiliation: Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fujimori
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado.
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.affiliation: Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan. okayasu.ryuichi@qst.go.jp.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okayasu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D004247:DNA; D059766:DNA End-Joining Repair; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen / Q000378:metabolism; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; D004247:DNA; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D000072200:Ku Autoantigen; D011493:Protein Kinase C; D011720:Pyrazoles; D051135:Rad51 Recombinase; D011838:Radiation-Sensitizing Agents; C000596495:pimitespib