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Apoptosis induced by topoisomerase inhibitors

Olivier Sordet1, Qasim A Khan, Kurt W Kohn

  • 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.

Current Medicinal Chemistry. Anti-Cancer Agents
|May 29, 2003
PubMed

Insights

Topoisomerase inhibitors trigger apoptosis through DNA damage, activating caspase pathways and involving DNA sensors like ATM and ATR. These pathways regulate cell death, repair, and cell cycle arrest, ultimately leading to programmed cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Topoisomerase inhibitors are potent inducers of apoptosis (programmed cell death).
  • Apoptosis induction involves caspase activation, mitochondrial pathways, and sometimes death receptors like Fas.
  • Cellular responses are regulated by upstream pathways sensing DNA damage.

Purpose of the Study:

  • To review the molecular pathways linking topoisomerase inhibitor-induced DNA damage to apoptosis.
  • To elucidate the roles of key regulatory proteins and kinases in this process.
  • To highlight the involvement of DNA sensors and downstream effectors in cell death.

Main Methods:

  • Literature review of molecular mechanisms.
  • Analysis of signaling pathways involved in DNA damage response.
  • Discussion of kinase and transcription factor involvement in apoptosis.

Main Results:

  • Topoisomerase inhibitors induce DNA lesions, activating DNA sensors (DNA-PK, ATM, ATR).
  • These sensors phosphorylate downstream kinases (Chk2, c-Abl) and transcription factors (p53, NF-kappaB).
  • Pro-apoptotic (Chk2, c-Abl, SAPK/JNK) and survival (PI3K-Akt) pathways are modulated, leading to caspase activation and apoptosis.
  • Topoisomerases may also contribute to chromatin fragmentation during apoptosis execution.

Conclusions:

  • Topoisomerase inhibitors initiate a complex network of signaling pathways culminating in apoptosis.
  • DNA damage response kinases and downstream effectors play critical roles in mediating cell death.
  • Understanding these pathways is crucial for developing targeted cancer therapies.

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