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

Fortunato Ciardiello, Rosa Caputo, Gaetano Borriello, Donatella Del Bufalo, Annamaria Biroccio, Gabriella Zupi, A. Raffaele Bianco, Giampaolo Tortora

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Abstract

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-et (TGF-et). 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. ZD 1839 inhibited the growth in soft agar of all 3 clones in a dose-dependent manner (IC50 of approximately 0.1 μM). This effect was accompanied by a dose-dependent inhibition of EGFR tyrosine autophosphorylation and of the production of TGF-α, 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 co-operative growth inhibition as well as apoptosis potentiation were observed. Combined treatment with IDN 5109 and ZDI839 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.

Original languageEnglish
Pages (from-to)463-469
Number of pages7
JournalInternational Journal of Cancer
Volume98
Issue number3
DOIs
Publication statusPublished - Mar 20 2002

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docetaxel
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Taxoids
Breast Neoplasms
Clone Cells
Paclitaxel
MCF-7 Cells
Growth
Neomycin
Transforming Growth Factors
Fibroblast Growth Factor 2
Doxorubicin
Vascular Endothelial Growth Factor A
Inhibitory Concentration 50
Agar
Tyrosine
Estrogens
gefitinib
taxane

Keywords

  • Breast cancer
  • Epidermal growth factor receptor
  • ZD1839

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

ZD1839 (Iressa), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells. / Ciardiello, Fortunato; Caputo, Rosa; Borriello, Gaetano; Del Bufalo, Donatella; Biroccio, Annamaria; Zupi, Gabriella; Bianco, A. Raffaele; Tortora, Giampaolo.

In: International Journal of Cancer, Vol. 98, No. 3, 20.03.2002, p. 463-469.

Research output: Contribution to journalArticle

Ciardiello, Fortunato ; Caputo, Rosa ; Borriello, Gaetano ; Del Bufalo, Donatella ; Biroccio, Annamaria ; Zupi, Gabriella ; Bianco, A. Raffaele ; Tortora, Giampaolo. / ZD1839 (Iressa), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells. In: International Journal of Cancer. 2002 ; Vol. 98, No. 3. pp. 463-469.
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abstract = "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-et (TGF-et). 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. ZD 1839 inhibited the growth in soft agar of all 3 clones in a dose-dependent manner (IC50 of approximately 0.1 μM). This effect was accompanied by a dose-dependent inhibition of EGFR tyrosine autophosphorylation and of the production of TGF-α, 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 co-operative growth inhibition as well as apoptosis potentiation were observed. Combined treatment with IDN 5109 and ZDI839 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.",
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