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DNA-Dependent Protein Kinase Is Inhibited by Trifluoperazine

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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 μM TFP. DNA-PKcs and Ku86 cleavage were evident in U-1810 cells after 30 min incubation with 100 μM 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.

References (30)

  • C. Klee et al.

    Calmodulin

    Adv. Protein Chem.

    (1982)
  • A. Means et al.

    Regulatory functions of calmodulin

    Pharmacol. Ther.

    (1991)
  • P. Charp et al.

    Inhibition of DNA repair by trifluoperazine

    Biochim. Biophys. Acta

    (1985)
  • F. Sirzén et al.

    DNA-dependent protein kinase content and activity in lung carcinoma cell lines: Correlation with intrinsic radiosensitivity

    Eur. J. Cancer

    (1999)
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    Abbreviations used: DNA-PK, DNA-dependent protein kinase; TFP, trifluoperazine, DSB, double strand break; ICE, interleukin-1β-converting enzyme; CPZ, chlorpromazine; PZ, promazine; TFPZ, triflupromazine; FF, fluphenazine; FPX, flupentixol; TUNEL, TdT-mediated dUTP-biotin nick end labelling; SDS, sodium dodecyl sulphate; TBS, Tris-buffered saline.

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