Critical role of both p27^KIP1and p21^CIP1/WAF1 in the antiproliferative effect of ZD1839 (‘Iressa’), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells

Abstract

High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of squamous-cell carcinomas of head and neck (SCCHN). ZD1839 ('Iressa') is an orally active, selective EGFR-TKI (EGFR-tyrosine kinase inhibitor) that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. We have demonstrated that ZD1839 induces growth arrest in SCCHN cell lines by inhibiting EGFR-mediated signaling. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest together with a partial G2/M block; this was associated with increased expression of both p27(KIP1) and p21(CIP1/WAF1) cyclin-dependent kinase (CDK) inhibitors. The activity of CDK2, the main target of CIP/KIP CDK inhibitors, was reduced in a dose-dependent fashion after 24 h of ZD1839 treatment and this effect correlated to the increased amount of p27(KIP1) and p21(CIP1/WAF1) proteins associated with CDK2-cyclin-E and CDK2-cyclin-A complexes. In addition, ZD1839-induced growth inhibition was significantly reduced in cell transfectants expressing p27(KIP1) or p21(CIP1/WAF1) antisense constructs. Overall, these results as well as the timing of the effect of ZD1839 on G1 arrest and p27(KIP1) and p21(CIP1/WAF1) upregulation, suggest a mechanistic connection between these events.

HER1-ECD vaccination dispenses with emulsification to elicit HER1-specific anti-proliferative effects

“…7 Furthermore, preclinical studies using others specific agents as cetuximab, gefitinib and erlotinib have demonstrated its ability to inhibit tumor cell proliferation inducing an arrest in G 1 phase. 22 Although G 0 /G 1 cells percent after treatment with non-emulsive formulation is lower than achieved for emulsive formulation, cell cycle arrest is also successful since not only G 0 /G1 cells percent increases but also G 2 /M and S cells percent decreased. G 2 /M phase is especially important because its gather cells near to undergo mitosis and subsequently proliferation.…”

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

“…Regulation of p27 kip1 expression and/or intracellular localization is one of the principal mechanisms trough which anti-EGFR and anti-ErbB-2 drugs block cell cycle progression in cancer cells [33][34][35][36][37].…”

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

“…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). In addition, gefitinib has been suggested to decrease the expression levels of proangiogenic factors, such as vascular endothelial growth factor and basic fibroblast growth factor in tumour cells, to inhibit migration and tube formation of endothelial cells and to reduce the invasive potential of tumour cells (Ciardiello et al, 2001;Bianco et al, 2002;Fujimura et al, 2002;Hirata et al, 2002).…”