title: Ciprofloxacin as a potential radio-sensitizer to tumor cells and a radio-protectant for normal cells: differential effects on γ-H2AX formation, p53 phosphorylation, Bcl-2 production, and cell death.
abstract: Ionizing radiation increases cell mortality in a dose-dependent manner. Increases in DNA double strand breaks, γ-H2AX, p53 phophorylation, and protein levels of p53 and Bax also occur. We investigated the ability of ciprofloxacin (CIP), a widely prescribed antibiotic, to inhibit DNA damage induced by ionizing radiation. Human tumor TK6, NH32 (p53 (-/-) of TK6) cells, and human normal peripheral blood mononuclear cells (PBMCs) were exposed to 2-8 Gy (60)Co-γ-photon radiation. γ-H2AX (an indicator of DNA strand breaks), phosphorylated p53 (responsible for cell-cycle arrest), Bcl-2 (an apoptotic protein, and cell death were measured. Ionizing irradiation increased γ-H2AX amounts in TK6 cells (p53(+/+)) within 1 h in a radiation dose-dependent manner. CIP pretreatment and posttreatment effectively inhibited the increase in γ-H2AX. CIP pretreatment reduced Bcl-2 production but promoted p53 phosphorylation, caspase-3 activation and cell death. In NH32 cells, CIP failed to significantly inhibit the radiation-induced γ-H2AX increase, suggesting that CIP inhibition involves in p53-dependent mechanisms. In normal healthy human PBMCs, CIP failed to block the radiation-induced γ-H2AX increase but effectively increased Bcl-2 production, but blocked the phospho-p53 increase and subsequent cell death. CIP increased Gadd45α, and enhanced p21 protein 24 h postirradiation. Results suggest that CIP exerts its effect in TK6 cells by promoting p53 phosphorylation and inhibiting Bcl-2 production and in PBMCs by inhibiting p53 phosphorylation and increasing Bcl-2 production. Our data are the first to support the view that CIP may be effective to protect normal tissue cells from radiation injury, while enhancing cancer cell death in radiation therapy.
authors.affiliation: Radiation Combined Injury Program, Scientific Research Department, Armed Forces Radiobiology Research Institute, Bethesda, MD, 20889-5603, USA, juliann.kiang@usuhs.edu.
authors.forename: Juliann G
authors.initials: JG
authors.lastname: Kiang
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Garrison
authors.forename: Joan T
authors.initials: JT
authors.lastname: Smith
authors.forename: Risaku
authors.initials: R
authors.lastname: Fukumoto
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002939:Ciprofloxacin / Q000008:administration & dosage*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000528:radiation effects; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D019253:Proto-Oncogene Proteins c-bcl-2; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002939:Ciprofloxacin