Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells

BMC Cancer. 2013 Jun 19;13:297. doi: 10.1186/1471-2407-13-297.

Abstract

Background: Over-expression of epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor (IGF-1R) have been shown to closely correlate with radioresistance of breast cancer cells. This study aimed to investigate the impact of co-inhibition of EGFR and IGF-1R on the radiosensitivity of two breast cancer cells with different profiles of EGFR and IGF-1R expression.

Methods: The MCF-7 (EGFR +/-, IGF-1R +++) and MDA-MB-468 (EGFR +++, IGF-1R +++) breast cancer cell lines were used. Radiosensitizing effects were determined by colony formation assay. Apoptosis and cell cycle distribution were measured by flow cytometry. Phospho-Akt and phospho-Erk1/2 were quantified by western blot. In vivo studies were conducted using MDA-MB-468 cells xenografted in nu/nu mice.

Results: In MDA-MB-468 cells, the inhibition of IGF-1R upregulated the p-EGFR expression. Either EGFR (AG1478) or IGF-1R inhibitor (AG1024) radiosensitized MDA-MB-468 cells. In MCF-7 cells, radiosensitivity was enhanced by AG1024, but not by AG1478. Synergistical radiosensitizing effect was observed by co-inhibition of EGFR and IGF-1R only in MDA-MB-468 cells with a DMF10% of 1.90. The co-inhibition plus irradiation significantly induced more apoptosis and arrested the cells at G0/G1 phase in MDA-MB-468 cells. Only co-inhibition of EGFR and IGF-1R synergistically diminished the expression of p-Akt and p-Erk1/2 in MDA-MB-468 cells. In vivo studies further verified the radiosensitizing effects by co-inhibition of both pathways in a MDA-MB-468 xenograft model.

Conclusion: Our data suggested that co-inhibition of EGFR and IGF-1R synergistically radiosensitized breast cancer cells with both EGFR and IGF-1R high expression. The approach may have an important therapeutic implication in the treatment of breast cancer patients with high expression of EGFR and IGF-1R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Breast Neoplasms / radiotherapy*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • G1 Phase Cell Cycle Checkpoints / radiation effects
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Radiation Tolerance / drug effects*
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Tumor Stem Cell Assay
  • Tyrphostins / pharmacology*
  • Tyrphostins / therapeutic use

Substances

  • Enzyme Inhibitors
  • Quinazolines
  • Tyrphostins
  • tyrphostin AG 1024
  • RTKI cpd
  • ErbB Receptors
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt