Mechanisms of enhancement of cytotoxicity in etoposide and ionising radiation-treated cells by the protein kinase inhibitor wortmannin

Eur J Cancer. 2000 Mar;36(4):535-41. doi: 10.1016/s0959-8049(99)00311-1.

Abstract

We have investigated the effects of the protein kinase inhibitor wortmannin (WM) on the cytotoxic mechanisms of etoposide and ionising radiation (IR) in the Chinese hamster ovary K1 (CHO-K1) cell line, and its radiation-sensitive derivative, xrs-6, which is defective in DNA-dependent protein kinase (DNA-PK) function. WM potentiated the cytotoxicity of etoposide and IR in CHO-K1 cells approximately 1.6 and 3-fold, respectively, and this potentiation was abolished in xrs-6 cells, which were themselves more sensitive to etoposide and IR alone. WM partially inhibited the repair of etoposide-induced DNA double-strand breaks. Etoposide treatment caused a biphasic inhibition of DNA synthesis in both cell lines, and this was abrogated by co-incubation with WM. These data suggest that WM inhibits in intact cells both DNA-PK and either or both the ataxia telangiectasia (AT) and AT-related gene products ATM and ATR.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / therapeutic use*
  • Animals
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Ataxia Telangiectasia Mutated Proteins
  • CHO Cells / drug effects*
  • Cell Cycle Proteins
  • Cricetinae
  • DNA Repair / drug effects
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Drug Synergism
  • Enzyme Inhibitors / therapeutic use
  • Etoposide / therapeutic use*
  • Female
  • Humans
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Survival Analysis
  • Tumor Suppressor Proteins
  • Wortmannin

Substances

  • Androstadienes
  • Antineoplastic Agents, Phytogenic
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • Etoposide
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • Wortmannin