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

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-␣ (TGF-␣). 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 M). This effect was accompanied by a dose-dependent inhibition of EGFR tyrosine autophosphorylation and of the production of TGF-␣, 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.

Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells

“…Blockade of the EGFR signalling pathways results in not only retardation of cell cycle progression but also induction of apoptosis in EGFR-expressing tumour cells. It has been suggested that the cell cycle retardation is mediated by an increase in the expression level of a CDKI p27 (Moasser et al, 2001;Albanell et al, 2002;Janne et al, 2002), and that the induction of apoptosis is mediated by a decrease in the expression level of an antiapoptotic protein Bcl-2 Ciardiello et al, 2002;Nicholson et al, 2002) or by activation of a proapoptotic protein BAD (Gilmore et al, 2002). Very recently, it has been reported that the EGFR-TKI gefitinib increases both p27 and p21 proteins associated with CDK2 -cyclin-E and CDK2 -cyclin-A complexes in HER1-overexpressing head and neck squamous carcinoma cells (Di Gennaro et al, 2003).…”

“…Actin or a-tubulin was used as the internal control. radiation or cytotoxic agents, such as taxanes and cisplatin, synergistically inhibit the growth of tumour cells both in vitro and in vivo (Ciardiello et al, 2000;Sirotnak et al, 2000;Ciardiello et al, 2001;Bianco et al, 2002;Ciardiello et al, 2002;Huang et al, 2002;Magne et al, 2002;Williams et al, 2002). However, no synergistic or additive activity has been reported with gefitinib and a cytotoxic agent in phase III clinical trials Johnson et al, 2002).…”

“…Recent studies have suggested that gefitinib induces cell cycle retardation and apoptosis, and inhibits the growth of several types of human cancer cells expressing EGFR both in vitro and in vivo (Ciardiello et al, 2000;Sirotnak et al, 2000;Ciardiello et al, 2001;Moasser et al, 2001;Moulder et al, 2001;Bianco et al, 2002;Ciardiello et al, 2002;Fujimura et al, 2002;Huang et al, 2002;Janne et al, 2002;Magne et al, 2002;Williams et al, 2002). In addition, human breast cancer cells overexpressing HER2 or acquiring resistance to the oestrogen receptor (ER) antagonist, fulvestrant (Faslodex,ICI 182,780), have been reported to be particularly sensitive to gefitinib (McClelland et al, 2001;Moulder et al, 2001).…”

The clinicopathological significance of Bax and Bcl-2 protein expression with tumor infiltrating lymphocytes in ovarian carcinoma

“…There are various mechanisms underlying taxane resistance that have been previously described [27]. In several in vitro studies, it was demonstrated that excessive Bcl-2 expression or impaired phosphorylation was responsible for taxane (docetaxel and paclitaxel) resistance; however, an opposite finding was reported by Ferlini et al, who suggested that Bcl-2 down regulation was responsible for paclitaxel resistance [28,29,30]. Additional conflicting results from several clinical studies have been reported.…”

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

“…Small molecule tyrosine kinase inhibitors (e.g., anilinoquinazoline compounds such as gefitinib and erlotinib), which are ATP analogues, 2,3,34,46,51 have been shown to exhibit growth inhibitory effects against a wide variety of human tumors. [13][14][15][16][17] The RTK inhibition approach has shown promise in some clinical trials, but results have been quite mixed. 19 In particular, despite the promise in a small (demographic) subpopulation with significantly advanced disease, clinical responses to gefitinib and erlotinib varied among population samples.…”