| RRC ID |
65872
|
| 著者 |
Lee Y, Sunada S, Hirakawa H, Fujimori A, Nickoloff JA, Okayasu R.
|
| タイトル |
TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation.
|
| ジャーナル |
Mol Cancer Ther
|
| 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.
|
| 巻・号 |
16(1)
|
| ページ |
16-24
|
| 公開日 |
2017-1-1
|
| DOI |
10.1158/1535-7163.MCT-16-0573
|
| PII |
1535-7163.MCT-16-0573
|
| PMID |
28062703
|
| PMC |
PMC5221699
|
| MeSH |
Animals
Benzamides / pharmacology*
Carbon Radioisotopes*
Cell Line, Tumor
DNA
DNA End-Joining Repair
Disease Models, Animal
Dose-Response Relationship, Drug
Dose-Response Relationship, Radiation
Gene Expression Regulation, Neoplastic
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HeLa Cells
Histones / metabolism
Humans
Ku Autoantigen / metabolism
Mice
Protein Kinase C / metabolism
Pyrazoles / pharmacology*
Rad51 Recombinase / genetics
Rad51 Recombinase / metabolism
Radiation Tolerance / drug effects*
Radiation, Ionizing*
Radiation-Sensitizing Agents / pharmacology*
X-Rays*
Xenograft Model Antitumor Assays
|
| IF |
5.615
|
| リソース情報 |
| ヒト・動物細胞 |
HFL-I(RCB0521) |
