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首页> 外文期刊>Molecular cancer therapeutics >TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation
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TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation

机译：TAS-116，一种新型HSP90抑制剂，选择性地增强人癌细胞的放射敏感性至X射线和碳离子辐射

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摘要

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 gamma-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. (C) 2016 AACR.
机译：HSP90抑制剂已被调查为单药治疗中的癌症治疗剂和增强放疗;然而，早期HSP90抑制剂的严重不良反应限制了其发展。 TAS-116是一种新的HSP90抑制剂，具有比其他HSP90抑制剂较低的不良反应，以及这里，我们研究了TAS-116在低线性能量转移（Let）X射线和高的碳离子辐照的人癌细胞中的辐射敏化效应和小鼠肿瘤异种移植物。 Tas-116降低了X射线和碳离子照射的人类癌细胞系（HeLa和H1299细胞）的细胞存活，类似于其他HSP90抑制剂，它不会影响非癌症的人成纤维细胞的放射敏感性。 TAS-116增加了辐射诱导的γ-H2AX焦点的数量，并延迟了DNA双链断裂（DSB）的修复。 TAS-116减少了通过同源重组（RAD51）和非博学终端接合（Ku，DNA-PKC）介导DSB修复的蛋白质的表达，并抑制了Rad51焦点的形成和DNA-PKC的磷酸化/活化。 TAS-116还降低了CDC25细胞周期进展标记物的表达，显着增加了G2-M骤停。与碳离子和Tas-116的小鼠肿瘤异种移植物的组合治疗显示出肿瘤生长的有希望的延迟与个体治疗相比。这些结果表明，通过抑制两个主要的DSB修复途径，TAS-116通过抑制两种主要的DSB修复途径来放射到X射线和碳离子中，并且这些效果伴随着标记的细胞周期停滞。组合TAS-116 +碳离子放射治疗的有希望的肿瘤异种移植物的结果证明了使用低或高的放射辐射的放射治疗的辅助探索。 （c）2016 AACR。

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  • 来源
    《Molecular cancer therapeutics》 |2017年第1期|共9页
  • 作者

    Lee Younghyun; Sunada Shigeaki; Hirakawa Hirokazu; Fujimori Akira; Nickoloff Jac A.; Okayasu Ryuichi;

  • 作者单位

    Natl Inst Radiol Sci Dept Basic Med Sci Radiat Damages Inage Ku 4-9-1 Anagawa Chiba 2638555;

    Natl Inst Radiol Sci Dept Basic Med Sci Radiat Damages Inage Ku 4-9-1 Anagawa Chiba 2638555;

    Natl Inst Radiol Sci Dept Basic Med Sci Radiat Damages Inage Ku 4-9-1 Anagawa Chiba 2638555;

    Natl Inst Radiol Sci Dept Basic Med Sci Radiat Damages Inage Ku 4-9-1 Anagawa Chiba 2638555;

    Colorado State Univ Dept Environm &

    Radiol Hlth Sci Ft Collins CO 80523 USA;

    Natl Inst Radiol Sci Dept Basic Med Sci Radiat Damages Inage Ku 4-9-1 Anagawa Chiba 2638555;

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  • 正文语种 eng
  • 中图分类 肿瘤学;
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