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ZD1839 (IRESSA), an EGFR‐selective tyrosine kinase inhibitor, enhances taxane activity in bcl‐2 overexpressing, multidrug‐resistant MCF‐7 ADR human breast cancer cells
Author(s) -
Ciardiello Fortunato,
Caputo Rosa,
Borriello Gaetano,
Del Bufalo Donatella,
Biroccio Annamaria,
Zupi Gabriella,
Bianco A. Raffaele,
Tortora Giampaolo
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10230
Subject(s) - docetaxel , cancer research , growth inhibition , tyrosine kinase inhibitor , taxane , paclitaxel , gefitinib , biology , tyrosine kinase , epidermal growth factor receptor , pharmacology , medicine , apoptosis , cancer , breast cancer , receptor , biochemistry
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‐α (TGF‐α). 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 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 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. © 2002 Wiley‐Liss, Inc.