Retracted: 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

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 TSUPr1). 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 mM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC 50 = 0.8-2.0 mM). 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 EGFRdriven androgen independence. ' 2005 Wiley-Liss, Inc. Key words: prostate cancer; hormonal therapy; EGFR; androgenindependent tumorsIn industrialized countries, prostate cancer (PCa) is the most frequently occurring malignancy in men, representing the second highest cause of cancer-related death. PCa usually begins as an androgen-sensitive, androgen-dependent (AD), nonmetastatic cancer, which without intervention may follow a gradual transition into a highly metastatic and then androgen-insensitive (AI) variety. The androgen receptor (AR) is a nuclear receptor that cooperates with multiple proteins to exert its biologic function. Upon binding to the ligand testosterone/5 -dihydrotestosterone (DHT), the AR can bind to the androgen response element (ARE) on the 5 0 promoter of target genes, resulting in the modulation of cell growth. Until relatively recent times, endocrine response pathways in PCa were described solely in terms of the intracellular pathways used by the androgens and the subsequent destructive effects exerted on AR signaling by antihormonal treatments. 1 It is widely accepted that androgens promote tumor growth by binding to ARs and acting as nuclear transcription factors that regulate the expression of genes involved in cell proliferation and survival mechanisms. In contrast, hormonal therapies promote tumor regression either by reducing the amount of androgens available to the tumor cells or...

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

“…EGFR signalling might be one of the most critical signalling mechanisms for cancer cells, including prostate cancer cells [1,3,10]. To investigate the effects of EGFR on PC3 cells, we analysed signalling molecules Figure 2.…”

“…EGFR has a critical role in tumour growth, and prostate tissue becomes more susceptible to the growth-promoting action of EGF family growth factors during androgen withdrawal [1,2]. The general inhibition of tyrosine kinase signalling pathways provides a therapeutic advantage against prostate cancer metastasis [3]. Therefore, inhibiting the activation of growth factor receptors, especially that of EGFR, may be a promising strategy for the treatment of prostate cancer.…”

Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro

“…Although an in vitro investigation had shown an additive antitumor effect of blocking both tyrosine kinase pathway and androgen receptor pathway by combining gefitinib with bicalutamide (17), clinical trials did not show similar benefit. These trials involved dual epidermal growth factor receptor/HER2 tyrosine kinase inhibitor gefitinib but failed to provide additional clinical advantage over docetaxel and estramustine in prostate cancer (18,19).…”

Akacid-medical-formulation, a novel biocidal oligoguanidine with antitumor activity reduces S-phase in prostate cancer cell lines through the Erk 1/2 mitogen-activated protein kinase pathway

“…Additionally, AR-coactivators such as SRC1, TIF2, ARA70 (13,14), oncogenes [e.g. Her2/NEU (15)], and cytokines like interleukin 6 (IL-6), insulin like growth factor I (IGF-I), and epidermal growth factor (EGF) (16,17) are known to enhance AR-signaling in a synergistic or, in the absence of androgens, ligand-independent manner.…”