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

Producción científica: Articlerevisión exhaustiva

32 Citas (Scopus)


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.

Idioma originalEnglish (US)
Páginas (desde-hasta)6200-6208
Número de páginas9
PublicaciónCancer Research
EstadoPublished - dic 1 2012
Publicado de forma externa

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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