p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase

  • Authors:
    • André Fedier
    • Ahmed Moawad
    • Urs Haller
    • Daniel Fink
  • View Affiliations

  • Published online on: November 1, 2003     https://doi.org/10.3892/ijo.23.5.1431
  • Pages: 1431-1437
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Abstract

DNA-dependent protein kinase (DNA-PK) is involved in non-homologous end joining which repairs DNA double-strand breaks introduced by irradiation and radiomimetic agents. DNA-PK interacts with p53 but may also have p53-independent functions. The present study investigated whether disruption of the gene for the catalytic subunit DNA-PKcs affects chemosensitivity in p53-deficient cells. Drug sensitivity of DNA-PKcs+/+/p53+/+, DNA-PKcs+/+/p53−/−, DNA-PKcs−/−/p53+/+, and DNA-PKcs−/−/p53−− mouse lung-fibroblasts was determined by the MTT assay, the clonogenic assay, and trypan blue exclusion. Susceptibility to apoptosis was determined by DNA fragmentation (TUNEL) and by caspase-3 cleavage. We show that p53-deficient cells were 2 to 3-fold resistant to treatment with doxorubicin, epirubicin, cisplatin, and docetaxel as compared to wild-type cells. We further demonstrate that the additional loss of DNA-PKcs function in p53-deficient cells resulted in a 2-fold increase in sensitivity to doxorubicin and epirubicin as documented by the MTT assay, clonogenic assay, and trypan blue exclusion. Doxorubicin-induced hypersensitivity in these cells correlated with a transient G2/M checkpoint activation but did not seem to correlate with apoptosis. The data indicate that additional loss of DNA-PKcs in p53-deficient cells reverses anthracycline-resistance imposed by p53-deficiency, and that DNA-PKcs modulates p53-independent pathways responding to DNA damage induced by anthracyclines. They also indicate that processes other than apoptosis may contribute to the increased cytotoxicity to anthracyclines. DNA-PKcs may thus be a potential target for functional inhibition, which might increase the efficacy of some anti-tumour agents in the treatment of cancers mutated in the p53 gene.

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November 2003
Volume 23 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Fedier A, Moawad A, Haller U and Fink D: p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase. Int J Oncol 23: 1431-1437, 2003
APA
Fedier, A., Moawad, A., Haller, U., & Fink, D. (2003). p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase. International Journal of Oncology, 23, 1431-1437. https://doi.org/10.3892/ijo.23.5.1431
MLA
Fedier, A., Moawad, A., Haller, U., Fink, D."p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase". International Journal of Oncology 23.5 (2003): 1431-1437.
Chicago
Fedier, A., Moawad, A., Haller, U., Fink, D."p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase". International Journal of Oncology 23, no. 5 (2003): 1431-1437. https://doi.org/10.3892/ijo.23.5.1431