PMID- 10485486
OWN - NLM
STAT- MEDLINE
DCOM- 19990930
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 59
IP  - 17
DP  - 1999 Sep 1
TI  - Inhibition of ATM and ATR kinase activities by the radiosensitizing agent,
      caffeine.
PG  - 4375-82
AB  - Caffeine exposure sensitizes tumor cells to ionizing radiation and other
      genotoxic agents. The radiosensitizing effects of caffeine are associated with
      the disruption of multiple DNA damage-responsive cell cycle checkpoints. The
      similarity of these checkpoint defects to those seen in ataxia-telangiectasia
      (A-T) suggested that caffeine might inhibit one or more components in an A-T
      mutated (ATM)-dependent checkpoint pathway in DNA-damaged cells. We now show that
      caffeine inhibits the catalytic activity of both ATM and the related kinase, ATM 
      and Rad3-related (ATR), at drug concentrations similar to those that induce
      radiosensitization. Moreover, like ATM-deficient cells, caffeine-treated A549
      lung carcinoma cells irradiated in G2 fail to arrest progression into mitosis,
      and S-phase-irradiated cells exhibit radioresistant DNA synthesis. Similar
      concentrations of caffeine also inhibit gamma- and UV radiation-induced
      phosphorylation of p53 on Ser15, a modification that may be directly mediated by 
      the ATM and ATR kinases. DNA-dependent protein kinase, another ATM-related
      protein involved in DNA damage repair, was resistant to the inhibitory effects of
      caffeine. Likewise, the catalytic activity of the G2 checkpoint kinase, hChk1,
      was only marginally suppressed by caffeine but was inhibited potently by the
      structurally distinct radiosensitizer, UCN-01. These data suggest that the
      radiosensitizing effects of caffeine are related to inhibition of the protein
      kinase activities of ATM and ATR and that both proteins are relevant targets for 
      the development of novel anticancer agents.
FAU - Sarkaria, J N
AU  - Sarkaria JN
AD  - Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
      sarkaria.jann@mayo.edu
FAU - Busby, E C
AU  - Busby EC
FAU - Tibbetts, R S
AU  - Tibbetts RS
FAU - Roos, P
AU  - Roos P
FAU - Taya, Y
AU  - Taya Y
FAU - Karnitz, L M
AU  - Karnitz LM
FAU - Abraham, R T
AU  - Abraham RT
LA  - eng
GR  - CA52995/CA/NCI NIH HHS/United States
GR  - CA69709/CA/NCI NIH HHS/United States
GR  - CA76193/CA/NCI NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proteins)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 3G6A5W338E (Caffeine)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (ATR protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PRKDC protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
SB  - IM
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Caffeine/*pharmacology
MH  - Cell Cycle Proteins/*antagonists & inhibitors/physiology
MH  - DNA-Activated Protein Kinase
MH  - *DNA-Binding Proteins
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - Nuclear Proteins
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/physiology
MH  - Proteins/*antagonists & inhibitors/physiology/radiation effects
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Proteins
EDAT- 1999/09/15 00:00
MHDA- 1999/09/15 00:01
CRDT- 1999/09/15 00:00
PHST- 1999/09/15 00:00 [pubmed]
PHST- 1999/09/15 00:01 [medline]
PHST- 1999/09/15 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1999 Sep 1;59(17):4375-82.