A novel NGR-conjugated peptide targets DNA damage responses for radiosensitization
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.
Keywords: DNA damage responses, NGR, irradiation, NIP (NBS1 inhibitory peptide), radiosensitization.
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