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Abrogation of G2 checkpoint specifically sensitize p53 defective cells to cancer chemotherapeutic agents

Y Luo1, S K Rockow-Magnone, M K Joseph

  • 1Department 47S AP9A, Cancer Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.

Anticancer Research
|April 13, 2001
PubMed
Abstract

Insights

Checkpoint kinase 1 (Chk1) is crucial for DNA damage response. Inhibiting G2/M checkpoint regulators can enhance chemotherapy

Area of Science:

  • Cell cycle regulation
  • DNA damage response
  • Cancer therapeutics

Background:

  • Checkpoint kinase 1 (Chk1) activates after DNA damage.
  • Chk1 phosphorylates and inactivates Cdc25C, leading to G2 phase arrest.
  • Cdc25C and Cdc2 inactivation are essential for DNA damage-induced G2 arrest.

Purpose of the Study:

  • To investigate the role of G2/M checkpoint abrogators in DNA damage response.
  • To evaluate the combined effect of adriamycin with G2/M checkpoint inhibitors (staurosporine or UCNO1).
  • To assess the impact on cell cycle arrest and cell death in different cell lines.

Main Methods:

  • Treatment of 184B5 cell line and its E6 transformed variants with adriamycin.
  • Co-treatment with staurosporine or UCNO1 to abrogate the G2/M checkpoint.
  • Examination of G2 arrest and cell death induction.

Main Results:

  • Adriamycin induced p53 and p21 response and G1 arrest in 184B5 cells, but not in E6 transformed cells.
  • Staurosporine or UCNO1 abrogated adriamycin-induced G2 arrest in both cell lines.
  • Staurosporine or UCNO1 sensitized p53-incompetent cells to adriamycin.

Conclusions:

  • G2/M checkpoint abrogators can enhance the cytotoxic effects of chemotherapeutic agents.
  • This enhancement is potentially specific to tumor cells.
  • Combined therapy may offer a strategy to overcome chemoresistance.

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