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Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

✍ Scribed by Claudio Festuccia; Giovanni Luca Gravina; Adriano Angelucci; Danilo Millimaggi; Paola Muzi; Carlo Vicentini; Mauro Bologna

Publisher
John Wiley and Sons
Year
2005
Tongue
French
Weight
618 KB
Volume
115
Category
Article
ISSN
0020-7136

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✦ Synopsis

Abstract

Progression from an androgen‐dependent to an androgen‐independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR‐positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR‐positive cells (LNCaP, CWR22, CWR22R 2152 and AR‐transfected DU145 cell lines) compared with AR‐negative cells (DU145, PC3 and TSU‐Pr1). Moreover, in AR‐transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen‐independent DU145 cells. All AR‐positive PCa cell lines were sensitive to gefitinib (IC~50~ = 0.1–0.6 μM), whereas higher concentrations of bicalutamide were needed to reduce AR‐positive PCa cell line proliferation (IC~50~ = 0.8–2.0 μM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC~50~ of bicalutamide (approximately 10‐fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC~50~ of gefitinib (approximately 5‐fold). Taken together, our data suggest that in androgen‐dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFR‐driven androgen independence. © 2005 Wiley‐Liss, Inc.

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