title: Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy.
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.
authors.affiliation: Department of Medicine, University of Florida and Shands Health Care System, Gainesville, Florida, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williamson
authors.forename: Leah
authors.initials: L
authors.lastname: Damiani
authors.forename: Andrei
authors.initials: A
authors.lastname: Leitao
authors.forename: Chelin
authors.initials: C
authors.lastname: Hu
authors.forename: Helen
authors.initials: H
authors.lastname: Hathaway
authors.forename: Tudor
authors.initials: T
authors.lastname: Oprea
authors.forename: Larry
authors.initials: L
authors.lastname: Sklar
authors.forename: Montaser
authors.initials: M
authors.lastname: Shaheen
authors.forename: Julie
authors.initials: J
authors.lastname: Bauman
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002939:Ciprofloxacin / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D057809:HEK293 Cells; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D019895:Transposases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D019428:HIV Integrase Inhibitors; D002939:Ciprofloxacin; D011495:Histone-Lysine N-Methyltransferase; C510450:SETMAR protein, human; D019895:Transposases; D002945:Cisplatin