ZD1839 (IRESSA), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells

Int J Cancer. 2002 Mar 20;98(3):463-9. doi: 10.1002/ijc.10230.


Constitutive bcl-2 overexpression increases the tumorigenic and metastatic potential of doxorubicin-resistant, estrogen-independent, MCF-7 ADR human breast cancer cells. We evaluated the sensitivity to taxanes (paclitaxel, docetaxel and IDN 5109) of 2 bcl-2-overexpressing MCF-7 ADR clones and control neomycin-transfected MCF-7 ADR neo cells. The 2 bcl-2-overexpressing MCF-7 ADR clones were relatively resistant to all 3 taxanes, whereas the MCF-7 ADR neo cells were relatively resistant to paclitaxel and docetaxel, but sensitive to IDN 5109. We found that both MCF-7 ADR neo and bcl-2-overexpressing MCF-7 ADR clones express high levels of the epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor-alpha (TGF-alpha). Therefore, we tested the growth inhibitory effect of ZD1839 (Iressa, AstraZeneca, Macclesfield, UK), an orally active, selective EGFR tyrosine kinase inhibitor (EGFR-TKI) that is in clinical development. ZD1839 inhibited the growth in soft agar of all 3 clones in a dose-dependent manner (IC(50) of approximately 0.1 microm). This effect was accompanied by a dose-dependent inhibition of EGFR tyrosine autophosphorylation and of the production of TGF-alpha, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). To determine whether the blockade of EGFR signaling might affect the sensitivity of bcl-2-overexpressing MCF-7 ADR cells to taxanes, cells were treated with ZD1839 in combination with paclitaxel, docetaxel or IDN 5109, and dose-dependent cooperative growth inhibition as well as apoptosis potentiation were observed. Combined treatment with IDN 5109 and ZD1839 also resulted in a significant inhibition of bcl-2 expression in bcl-2-overexpressing MCF-7 ADR cells. These results demonstrate the ability of ZD1839 to overcome taxane resistance in a model of hormone-independent, multidrug-resistant, human breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Bridged-Ring Compounds / therapeutic use*
  • Cell Division / drug effects
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Enzyme Inhibitors / therapeutic use*
  • ErbB Receptors / metabolism*
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Gefitinib
  • Humans
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Quinazolines / therapeutic use*
  • Taxoids*
  • Transfection
  • Transforming Growth Factor alpha / metabolism
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism


  • Antineoplastic Agents
  • Bridged-Ring Compounds
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Quinazolines
  • Taxoids
  • Transforming Growth Factor alpha
  • Fibroblast Growth Factor 2
  • taxane
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Gefitinib