摘要
放疗是治疗肝细胞癌患者的重要策略之一。发展新的放疗敏化剂是一个关键问题,因为肝细胞癌的固有放射敏感性低。野生型NBS1抑制肽(wtNIP)可以通过取消ATM-NBS1相互作用并阻止DNA损伤应答来提高一些癌细胞系的放射敏感性。在此我们通过把CNGRC血管生成血管引导肽NGR和wtNIP肽相结合开发了一个新NGR接合肽(NGR-sR9-wtNIP)。我们测试了融合肽的内化,Hep3B细胞毒性,肿瘤定位和移植人肝细胞癌的裸鼠的毒性。我们也研究了NGR-sR9-wtNIP的放射增敏活性。我们发现NGR-sR9-wtNIP可以抑制放射诱导的NBS1磷酸化并诱导Hep3B细胞的放射敏化。与IR相结合,NGR-sR9-wtNIP明显抑制了移植小鼠的肿瘤生长。此外,我们的数据有力地证明了NGR-sR9-wtNIP具有用于肝细胞癌放疗的放射增敏潜力。
关键词: DNA损伤应答,NGR,放射,NIP(NBS1抑制肽),放射敏化
Current Cancer Drug Targets
Title:A novel NGR-conjugated peptide targets DNA damage responses for radiosensitization
Volume: 15 Issue: 6
Author(s): Jinlu Ma, Dan Zhang, Xia Ying, Ying Zhao, Chenchen He, Qing Zhu and Suxia Han
Affiliation:
关键词: DNA损伤应答,NGR,放射,NIP(NBS1抑制肽),放射敏化
摘要: Radiotherapy is one of the important treatment strategies for patients with advanced hepatocellular carcinomas. Developing novel sensitizers for radiotherapy is a key issue due to the low intrinsic radiosensitivity of hepatocellular carcinomas. It was reported the wild-type NBS1 inhibitory peptide (wtNIP) can increase radiosensitivity in several cancer cell lines by abrogating ATM-NBS1 interaction and interrupting cellular DNA damage response. Here, we developed a novel NGRconjugated peptide (NGR-sR9-wtNIP) through coupling the CNGRC angiogenic vessel-homing peptide NGR with the wtNIP peptide. Fusion peptide was tested for internalization, cytotoxicity in Hep3B cells and for tumor localization, and for toxicity in nude mice bearing human hepatocellular carcinomas xenografts. The radiosensitizing activity of NGR-sR9-wtNIP was investigated as well. We found that NGR-sR9-wtNIP can inhibit irradiation induced NBS1 phosphorylation and induce radiosensitization in Hep3B cells. When combined with IR, NGR-sR9-wtNIP suppressed tumor growth obviously in xenograft mice. In addition, the fusion peptide localized in tumor tissue specifically and barely led to any side effects on mice. Taken together, our data strongly suggest that NGRsR9- wtNIP has radiosensitizing potential for radiotherapy of hepatocellular carcinomas.
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Cite this article as:
Jinlu Ma, Dan Zhang, Xia Ying, Ying Zhao, Chenchen He, Qing Zhu and Suxia Han , A novel NGR-conjugated peptide targets DNA damage responses for radiosensitization, Current Cancer Drug Targets 2015; 15 (6) . https://dx.doi.org/10.2174/1568009615666150408114817
DOI https://dx.doi.org/10.2174/1568009615666150408114817 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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