Open Access

Switching p53-dependent growth arrest to apoptosis via the inhibition of DNA damage-activated kinases

  • Pavla Hublarova1,
  • Kristina Greplova2,
  • Jitka Holcakova1,
  • Borivoj Vojtesek1 and
  • Roman Hrstka1Email author
Cellular & Molecular Biology LettersAn International Journal201015:21

https://doi.org/10.2478/s11658-010-0021-5

Received: 6 January 2010

Accepted: 27 May 2010

Published: 4 June 2010

Abstract

Cisplatin and doxorubicin are widely used anticancer drugs that cause DNA damage, which activates the ATM-Chk2-p53 pathway in cancer cells. This activation leads to cell cycle block or apoptosis, depending on the nature of the DNA damage. In an attempt to enhance the effects of these agents, we inhibited ATM/ATR and Chk2, which are known upstream regulators of p53. The cancer cell lines A2780 and ARN8, bearing the wild-type p53 protein, were used to study changes in p53 activation and trans-activation. Our results suggest that the G1-checkpoint, normally activated by DNA damage, is functionally overcome by the action of kinase inhibitors that sensitize cells to apoptosis. Both inhibitors show these effects, albeit with variable intensity in different cell lines, which is promising for other studies and theoretically for use in clinical practice.

Key words

Protein p53 ATM/ATR kinases Chk2 Inhibitors of DNA damage-activated kinases Doxorubicin Cisplatin

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