title: Combination of nitric oxide stimulation with high-dose 18F-FDG promotes apoptosis and enhances radiation therapy of endothelial cells.
abstract: BACKGROUND
  High-dose (18)F-FDG can provide targeted nuclear therapy of cancer. Endothelial cell injury is a key determinant of tumor response to radiotherapy. Here, we tested the hypothesis that activation of endothelial cell glycolytic metabolism with nitric oxide can enhance the therapeutic effect of high-dose (18)F-FDG.
  
  
  METHODS
  Calf pulmonary artery endothelial (CPAE) cells were treated with graded doses of (18)F-FDG. Glycolysis was stimulated by 24 h of exposure to the nitric oxide donor, sodium nitroprusside (SNP). Cell viability was assessed by MTT and clonogenic assays. Apoptosis was evaluated by ELISA of cytosolic DNA fragments and Western blots of cleaved caspase-3.
  
  
  RESULTS
  SNP stimulation (0.1 and 1 mM) augmented CPAE cell (18)F-FDG uptake to 2.6- and 4.6-fold of controls without adverse effects. Treatment with 333 μCi/ml (18)F-FDG alone reduced viable cell number to 35.4% of controls by Day 3. Combining 0.1 mM SNP stimulation significantly enhanced the killing effect, reducing cell numbers to 19.2% and 39.2% of controls by 333 and 167 μCi/ml of (18)F-FDG, respectively. (18)F-FDG also suppressed clonogenic survival to 80.8% and 43.2% of controls by 83 and 167 μCi/ml, which was again intensified by SNP to 59.7% and 21.1% of controls. The cytotoxic effect of (18)F-FDG was attributed to induction of apoptosis as shown by increased cytosolic fragmented DNA and cleaved caspase-3 levels (26.4% and 30.7% increases by 167 μCi/ml). Combining SNP stimulation significantly increased both of these levels to 1.8-fold of control cells.
  
  
  CONCLUSIONS
  High-dose (18)F-FDG combined with nitric oxide-stimulated glycolysis is an effective method to inhibit endothelial cell survival and promote apoptosis. These results suggest a potential role of this strategy for targeted radiotherapy of angiogenic vasculature.
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Paik
authors.forename: Jin-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Jung
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Lee
authors.forename: Kyung-Han
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000494:pharmacology
chemical_list: D020030:Nitric Oxide Donors; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D009599:Nitroprusside; D009569:Nitric Oxide; D053148:Caspase 3