Department of Radiological Sciences, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
Department of Biology, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
Int J Mol Med. 2014 Mar;33(3):559-64. doi: 10.3892/ijmm.2013.1594. Epub 2013 Dec 19.
The molecular chaperone heat shock protein 90 (Hsp90) is involved in the maturation and stabilization of a wide range of oncogenic client proteins for oncogenesis and malignant cell proliferation, which renders this protein a promising target in the development of cancer therapeutics. PU-H71 is a purine-scaffold Hsp90 inhibitor with less toxicity in normal cells than in cancer cells. In this study, we examined the in vitro radiosensitizing activity and molecular mechanisms of action of PU-H71 in human lung cancer cell lines. PU-H71 enhanced the sensitivity of the SQ-5 and A549 cancer cells to radiation. When the cancer cells were pre-treated with PU-H71, the repair of DNA double-strand breaks (DSBs) was markedly inhibited after irradiation compared with the cells that were not pre-treated with PU-H71, as evaluated by counting the foci of phosphorylated histone H2AX (γ-H2AX). We further demonstrated that post-irradiation, PU-H71 inhibited Rad51 foci formation, a critical protein for the homologous recombination pathway of DNA DSB repair. These data indicate that targeting Hsp90 with PU-H71 may be novel therapeutic strategy for radioresistant carcinomas.
热休克蛋白 90（Hsp90）是一种分子伴侣，参与多种致癌客户蛋白的成熟和稳定，从而促进肿瘤发生和恶性细胞增殖，这使得该蛋白成为癌症治疗开发中有前途的靶标。PU-H71 是一种嘌呤支架 Hsp90 抑制剂，在正常细胞中的毒性低于癌细胞。在这项研究中，我们研究了 PU-H71 在人肺癌细胞系中的体外放射增敏活性和作用机制。PU-H71 增强了 SQ-5 和 A549 癌细胞对辐射的敏感性。当用 PU-H71 预处理癌细胞时，与未用 PU-H71 预处理的细胞相比，辐射后 DNA 双链断裂（DSB）的修复明显受到抑制，通过检测磷酸化组蛋白 H2AX（γ-H2AX）的焦点来评估。我们进一步证明，照射后，PU-H71 抑制 Rad51 焦点形成，Rad51 焦点形成是 DNA DSB 修复同源重组途径的关键蛋白。这些数据表明，用 PU-H71 靶向 Hsp90 可能是治疗辐射抗性癌的新策略。
