Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms

Mol Cancer Ther. 2004 May;3(5):621-32.

Abstract

Camptothecin and Adriamycin are clinically important inhibitors for topoisomerase (Topo) I and Topo II, respectively. The ataxia-telangiectasia mutated (ATM) product is essential for ionizing radiation-induced DNA damage responses, but the role of ATM in Topo poisons-induced checkpoints remains unresolved. We found that distinct mechanisms are involved in the activation of different cell cycle checkpoints at different concentrations of Adriamycin and camptothecin. Adriamycin promotes the G(1) checkpoint through activation of the p53-p21(CIP1/WAF1) pathway and decrease of pRb phosphorylation. Phosphorylation of p53(Ser20) after Adriamycin treatment is ATM dependent, but is not required for the full activation of p53. The G(1) checkpoint is dependent on ATM at low doses but not at high doses of Adriamycin. In contrast, the Adriamycin-induced G(2) checkpoint is independent on ATM but sensitive to caffeine. Adriamycin inhibits histone H3(Ser10) phosphorylation through inhibitory phosphorylation of CDC2 at low doses and down-regulation of cyclin B1 at high doses. The camptothecin-induced intra-S checkpoint is partially dependent on ATM, and is associated with inhibitory phosphorylation of cyclin-dependent kinase 2 and reduction of BrdUrd incorporation after mid-S phase. Finally, apoptosis associated with high doses of Adriamycin or camptothecin is not influenced by the absence of ATM. These data indicate that the involvement of ATM following treatment with Topo poisons differs extensively with dosage and for different cell cycle checkpoints.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Caffeine / pharmacology
  • Camptothecin / antagonists & inhibitors
  • Camptothecin / pharmacology
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • DNA Damage / drug effects*
  • DNA-Binding Proteins
  • Dose-Response Relationship, Drug
  • Doxorubicin / antagonists & inhibitors
  • Doxorubicin / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • G1 Phase / drug effects
  • G2 Phase / drug effects
  • Genes, cdc / drug effects*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Nuclear Proteins / metabolism
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • S Phase / drug effects
  • Topoisomerase I Inhibitors*
  • Topoisomerase II Inhibitors*
  • Tumor Suppressor Proteins

Substances

  • Antibiotics, Antineoplastic
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Guanine Nucleotide Exchange Factors
  • Nuclear Proteins
  • RCC1 protein, human
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Tumor Suppressor Proteins
  • Caffeine
  • Doxorubicin
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • Camptothecin