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.