Targeted inhibition of the epidermal growth factor receptor-tyrosine kinase by ZD1839 ('Iressa') induces cell-cycle arrest and inhibits proliferation in prostate cancer cells.
The epidermal growth factor (EGF) plays a role in the development of prostate cancer, which becomes essential after androgen resistance has emerged. The EGF receptor (EGFR) is therefore a potential target for anticancer therapy. We evaluated the effects of ZD1839 ('Iressa'), an orally active EGFR-tyrosine kinase inhibitor, on prostate cancer cell lines. The effects of ZD1839 were evaluated on the anchorage dependent and independent growth of androgen-responsive (LNCaP) and androgen-independent (DU145 and PC3) cells by a cell proliferation assay, cell counting, and soft agar analysis. Flow cytometric analysis and Western blotting were used to assess the effects on the cell-cycle and on protein expression levels, respectively. ZD1839 caused a dose- and time-dependent growth inhibition in all three cell lines. A dose-dependent supra-additive increase in growth inhibition was observed when ZD1839 was combined with the antiandrogen flutamide or ionizing radiation (IR). The antiproliferative effect of ZD1839 was mainly cytostatic and associated with a block in the G(0)/G(1) phase of the cell-cycle, evident after about 12 h of treatment. In the DU145 cells this block was associated with an increase in expression of the CDK inhibitor p27(Kip1), both in the cytoplasmic and nuclear fractions. The increase in p27(Kip1) was not evident in the LNCaP and PC3 cells. No changes were observed in the expression of cyclin D1 protein. These results demonstrate the antiproliferative effects of ZD1839 on the growth of prostate cancer cells and suggest that inhibition of EGFR-associated signal transduction pathway might represent a promising novel therapeutic strategy for the treatment of prostate cancer.
Sgambato
Alessandro
A
Centro di Ricerche Oncologiche "Giovanni XXIII"-Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, Italy.
Camerini
Andrea
A
Faraglia
Beatrice
B
Ardito
Raffaele
R
Bianchino
Gabriella
G
Spada
Daniele
D
Boninsegna
Alma
A
Valentini
Vincenzo
V
Cittadini
Achille
A
D000726:Androgen Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005485:Flutamide / Q000494:pharmacology; D000077156:Gefitinib; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms; D011799:Quinazolines / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005485:Flutamide; D066246:ErbB Receptors; D000077156:Gefitinib