Synergistic anti-neoplastic effect of AG1478 in combination with cisplatin or paclitaxel on human endometrial and ovarian cancer cells

AG1478, a potent inhibitor of epidermal growth factor receptor (EGFR), facilitates the induction of cell death in combination with a variety of cytotoxic and chemotherapeutic agents in certain human tumor cell lines. The purpose of this study was to elucidate the effect of AG1478 on three endometrial cancer and two ovarian cancer cell lines as compared to normal human endometrial epithelial cells. Cells were treated with various concentrations of AG1478 alone or in combination with the chemotherapeutic drugs cisplatin or paclitaxel, and the effect of AG1478 on cell growth, the cell cycle and apoptosis was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that all the cancer cell lines were sensitive to the growth-inhibitory effect of AG1478. Normal endometrial epithelial cells remained viable after treatment with AG1478 at the same doses as those which induced growth inhibition in the endometrial and ovarian cancer cells. Synergistic anti-neoplastic effects were obtained with a combination of AG1478 and cytostatic drugs. Cell-cycle analysis indicated that exposure to these drugs decreased the proportion of cells in the S-phase and increased the proportion in the sub G0/G1 fractions of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and by loss of mitochondrial transmembrane potential. These results suggest that AG1478 alone or in combination with chemotherapeutic drugs may be a novel therapeutic option for the treatment of endometrial and ovarian cancer.