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Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine

J N Sarkaria1, E C Busby, R S Tibbetts

  • 1Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA. sarkaria.jann@mayo.edu

Cancer Research
|September 15, 1999
PubMed

Insights

Caffeine enhances cancer cell sensitivity to radiation by disrupting DNA damage checkpoints. This effect stems from caffeine inhibiting key kinases like ATM and ATR, crucial for DNA repair and cell cycle control.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Caffeine is known to sensitize tumor cells to genotoxic agents like ionizing radiation.
  • This radiosensitization is linked to the disruption of DNA damage-responsive cell cycle checkpoints.
  • Similarities between caffeine's effects and defects in ataxia-telangiectasia (A-T) suggested a potential inhibition of ATM-dependent pathways.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying caffeine's radiosensitizing effects.
  • To determine if caffeine inhibits ATM (ataxia-telangiectasia mutated) and/or ATR (ATM and Rad3-related) kinases.
  • To explore the role of ATM and ATR inhibition in caffeine-induced radiosensitization and cell cycle checkpoint abrogation.

Main Methods:

  • Assessed the catalytic activity of ATM and ATR kinases in the presence of caffeine.
  • Examined the effects of caffeine on cell cycle progression in irradiated lung carcinoma cells (A549).
  • Measured the phosphorylation of p53 on Ser15 following gamma- and UV radiation in caffeine-treated cells.
  • Evaluated the impact of caffeine on other related kinases like DNA-dependent protein kinase and hChk1.

Main Results:

  • Caffeine inhibited the catalytic activity of both ATM and ATR kinases at concentrations relevant to radiosensitization.
  • Caffeine-treated cells failed to arrest in G2 phase after irradiation and exhibited radioresistant DNA synthesis in S-phase.
  • Caffeine reduced gamma- and UV radiation-induced p53 phosphorylation at Ser15.
  • DNA-dependent protein kinase and hChk1 showed relative resistance to caffeine's inhibitory effects.

Conclusions:

  • Caffeine's radiosensitizing properties are attributed to the inhibition of ATM and ATR protein kinase activities.
  • ATM and ATR are identified as key molecular targets mediating caffeine's effects on DNA damage response and radiosensitization.
  • These findings suggest ATM and ATR as potential targets for developing novel anticancer agents aimed at enhancing radiotherapy efficacy.

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