A phosphatidylinositol 3-kinase inhibitor wortmannin induces radioresistant DNA synthesis and sensitizes cells to bleomycin and ionizing radiation

Int J Cancer. 1998 Nov 23;78(5):642-7. doi: 10.1002/(sici)1097-0215(19981123)78:5<642::aid-ijc19>3.0.co;2-3.

Abstract

ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) have been shown to have sequences homologous to the catalytic domains of mammalian phosphatidylinositol 3-kinase (PI3-kinase). In order to determine the contribution of ATM and DNA-PKcs to the increased sensitivity of cells to DNA-damaging agents observed in the presence of PI3-kinase inhibitors, we examined the effects of a PI3-kinase inhibitor, wortmannin, on cellular sensitivity to bleomycin (BLM), mitomycin C (MMC), X-irradiation and ultraviolet (UV)-irradiation using 2 human tumor cell lines (T98G and A172), a human fibroblast cell line (LM217), an ataxia telangiectasia (AT) cell line (AT3BISV), a scid murine cell line (SCF) and a control murine cell line (CBF). Wortmannin sensitized all of the cells, including AT3BISV and SCF, to BLM and X-irradiation, but not to MMC or UV-irradiation. Hypersensitivity to BLM and X-irradiation and normal sensitivity to MMC and UV-irradiation are characteristic phenotypes of both AT and scid mice. DNA-dependent protein kinase (DNA-PK) activity was suppressed by wortmannin to 45-65% of the control values in all of the cells except SCF, in which DNA-PK activity was not detected. Wortmannin also induced radioresistant DNA synthesis, which is a cellular phenotype of AT, in T98G and SCF cells, but did not change the DNA synthesis rates after X-irradiation in AT3BISV. Our data suggest that wortmannin decreases the activities of both the ATM protein and DNA-PK, indicating that it might be of use as a sensitizing agent for radiotherapy and chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology*
  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins
  • Bleomycin / pharmacology*
  • Cell Cycle Proteins
  • DNA / biosynthesis*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Mice, SCID
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proteins / analysis
  • Radiation-Sensitizing Agents / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Wortmannin

Substances

  • Androstadienes
  • Antibiotics, Antineoplastic
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proteins
  • Radiation-Sensitizing Agents
  • Tumor Suppressor Proteins
  • Bleomycin
  • DNA
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • Wortmannin