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 language | English |
|---|---|
| Pages (from-to) | 463-469 |
| Number of pages | 7 |
| Journal | International Journal of Cancer |
| Volume | 98 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 20 2002 |
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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 journal › Article
}
TY - JOUR
T1 - ZD1839 (Iressa), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells
AU - Ciardiello, Fortunato
AU - Caputo, Rosa
AU - Borriello, Gaetano
AU - Del Bufalo, Donatella
AU - Biroccio, Annamaria
AU - Zupi, Gabriella
AU - Bianco, A. Raffaele
AU - Tortora, Giampaolo
PY - 2002/3/20
Y1 - 2002/3/20
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Epidermal growth factor receptor
KW - ZD1839
UR - http://www.scopus.com/inward/record.url?scp=0037139374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037139374&partnerID=8YFLogxK
U2 - 10.1002/ijc.10230
DO - 10.1002/ijc.10230
M3 - Article
C2 - 11920601
AN - SCOPUS:0037139374
VL - 98
SP - 463
EP - 469
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 3
ER -