Tyrphostin AG 1024 modulates radiosensitivity in human breast cancer cells

Br J Cancer. 2001 Dec 14;85(12):2017-21. doi: 10.1054/bjoc.2001.2171.

Abstract

Insulin-like growth factor-1 (IGF-1) plays an important growth-promoting effect by activating the PI3K/Akt signalling pathway, inhibiting apoptotic pathways and mediating mitogenic actions. Tyrphostin AG 1024, one selective inhibitor of IGF-1R, was used to evaluate effects on proliferation, radiosensitivity, and radiation-induced cell apoptosis in a human breast cancer cell line MCF-7. Exposure to Tyrphostin AG 1024 inhibited proliferation and induced apoptosis in a time-dependent manner, and the degree of growth inhibition for IC20 plus irradiation (4 Gy) was up to 50% compared to the control. Examination of Tyrphostin AG 1024 effects on radiation response demonstrated a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis. Western blot analysis indicated that Tyrphostin AG 1024-induced apoptosis was associated with a downregulation of expression of phospho-Akt1, increased expression of Bax, p53 and p21, and a decreased expression of bcl-2 expression, especially when combined with irradiation. To our knowledge, this is the first report showing that an IGF-1 inhibitor was able to markedly increase the response of tumour cells to ionizing radiation. These results suggest that Tyrphostin AG 1024 could be used as a potential therapeutic agent in combination with irradiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Cyclins / genetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Genes, bcl-2
  • Genes, p53
  • Humans
  • Insulin-Like Growth Factor I / physiology*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Radiation Tolerance / drug effects
  • Radiation-Sensitizing Agents / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / radiation effects
  • Tumor Stem Cell Assay
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tyrphostins / pharmacology*
  • bcl-2-Associated X Protein

Substances

  • BAX protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Radiation-Sensitizing Agents
  • Tumor Suppressor Protein p53
  • Tyrphostins
  • bcl-2-Associated X Protein
  • tyrphostin AG 1024
  • Insulin-Like Growth Factor I
  • Receptor Protein-Tyrosine Kinases
  • Receptor, IGF Type 1
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt