title: DNA-dependent protein kinase is inhibited by trifluoperazine.
abstract: The DNA-dependent protein kinase (DNA-PK) is a serine/threonine nuclear kinase, important for the repair of DNA double strand breaks (DSB). Cells defective in DNA-PK show increased sensitivity to ionising radiation and different DNA-damaging drugs, such as cisplatinum. Increased sensitivity to cisplatinum has previously been noted in the presence of phenothiazines. We tested a panel of phenothiazines and one thioxanthen for any influence upon the activity and expression of DNA-PK in a nonsmall cell lung cancer cell line, U-1810. The activity of DNA-PK was completely inhibited in cell lysate and in purified enzyme by 200 microM TFP. DNA-PKcs and Ku86 cleavage were evident in U-1810 cells after 30 min incubation with 100 microM TFP, along with changes in the cells consistent with apoptosis. Our study suggests that phenothiazines and thioxanthens, acting through DNA-PK, have the potential to enhance the effects of DNA damaging agents.
authors.affiliation: Division of Medical Radiation Biology, Karolinska Hospital, Stockholm, SE-171 76, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Eriksson
authors.forename: J
authors.initials: J
authors.lastname: Yachnin
authors.forename: R
authors.initials: R
authors.lastname: Lewensohn
authors.forename: A
authors.initials: A
authors.lastname: Nilsson
authors.forename: A
authors.initials: A
authors.lastname: Nilsso
mesh_terms: D015153:Blotting, Western; D002457:Cell Extracts; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014268:Trifluoperazine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D002457:Cell Extracts; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D014268:Trifluoperazine; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases