title: A novel NGR-conjugated peptide targets DNA damage responses for radiosensitization.
abstract: 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.
authors: Jinlu
authors: J
authors: Ma
authors: Dan
authors: D
authors: Zhang
authors: Xia
authors: X
authors: Ying
authors: Ying
authors: Y
authors: Zhao
authors: Chenchen
authors: C
authors: He
authors: Qing
authors: Q
authors: Zhu
authors: Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University Medical College, Xi'an, Shaanxi 710061, China. shan87@mail.xjtu.edu.cn.
authors: Suxia
authors: S
authors: Han
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; C526428:NGR peptide; D009687:Nuclear Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D011838:Radiation-Sensitizing Agents; D011993:Recombinant Fusion Proteins