Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells.

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.

Di Gennaro E ，Barbarino M ，Bruzzese F ，De Lorenzo S ，Caraglia M ，Abbruzzese A ，Avallone A ，Comella P ，Caponigro F ，Pepe S ，Budillon A ... -  《JOURNAL OF CELLULAR PHYSIOLOGY》

Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27(KIP1).

Patel V ，Lahusen T ，Leethanakul C ，Igishi T ，Kremer M ，Quintanilla-Martinez L ，Ensley JF ，Sausville EA ，Gutkind JS ，Senderowicz AM ... -  《CLINICAL CANCER RESEARCH》

G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells.

Akiyama T ，Yoshida T ，Tsujita T ，Shimizu M ，Mizukami T ，Okabe M ，Akinaga S ... -  《CANCER RESEARCH》

Targeted inhibition of the epidermal growth factor receptor-tyrosine kinase by ZD1839 ('Iressa') induces cell-cycle arrest and inhibits proliferation in prostate cancer cells.

Sgambato A ，Camerini A ，Faraglia B ，Ardito R ，Bianchino G ，Spada D ，Boninsegna A ，Valentini V ，Cittadini A ... -  《JOURNAL OF CELLULAR PHYSIOLOGY》

Molecular mechanisms of ZD1839-induced G1-cell cycle arrest and apoptosis in human lung adenocarcinoma A549 cells.

Chang GC ，Hsu SL ，Tsai JR ，Liang FP ，Lin SY ，Sheu GT ，Chen CY ... -  《BIOCHEMICAL PHARMACOLOGY》