Targeting the transposase domain of the DNA repair component metnase to enhance chemotherapy

Elizabeth A. Williamson, Leah Damiani, Andrei Leitao, Chelin Hu, Helen Hathaway, Tudor Oprea, Larry Sklar, Montaser Shaheen, Julie Bauman, Wei Wang, Jac A. Nickoloff, Suk Hee Lee, Robert Hromas

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23 Scopus citations

Abstract

Previous studies have shown that the DNA repair component Metnase (SETMAR) mediates resistance to DNA damaging cancer chemotherapy. Metnase has a nuclease domain that shares homology with the Transposase family. We therefore virtually screened the tertiary Metnase structure against the 550,000 compound ChemDiv library to identify small molecules that might dock in the active site of the transposase nuclease domain of Metnase. We identified eight compounds as possible Metnase inhibitors. Interestingly, among these candidate inhibitors were quinolone antibiotics and HIV integrase inhibitors, which share common structural features. Previous reports have described possible activity of quinolones as antineoplastic agents. Therefore, we chose the quinolone ciprofloxacin for further study, based on its wide clinical availability and low toxicity. We found that ciprofloxacin inhibits the ability of Metnase to cleave DNA and inhibits Metnase-dependent DNA repair. Ciprofloxacin on its own did not induce DNA damage, but it did reduce repair of chemotherapy-induced DNA damage. Ciprofloxacin increased the sensitivity of cancer cell lines and a xenograft tumor model to clinically relevant chemotherapy. These studies provide a mechanism for the previously postulated antineoplastic activity of quinolones, and suggest that ciprofloxacin might be a simple yet effective adjunct to cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)6200-6208
Number of pages9
JournalCancer Research
Volume72
Issue number23
DOIs
StatePublished - Dec 1 2012

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Williamson, E. A., Damiani, L., Leitao, A., Hu, C., Hathaway, H., Oprea, T., Sklar, L., Shaheen, M., Bauman, J., Wang, W., Nickoloff, J. A., Lee, S. H., & Hromas, R. (2012). Targeting the transposase domain of the DNA repair component metnase to enhance chemotherapy. Cancer Research, 72(23), 6200-6208. https://doi.org/10.1158/0008-5472.CAN-12-0313