Takai Noriyuki, Ueda Tami, Nishida Masakazu, Nasu Kaei, Narahara Hisashi
Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, Oita 879-5593, Japan.
Mol Med Rep. 2010 May-Jun;3(3):479-84. doi: 10.3892/mmr_00000284.
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.
AG1478是一种有效的表皮生长因子受体（EGFR）抑制剂，在某些人类肿瘤细胞系中，它与多种细胞毒性和化疗药物联合使用时，可促进细胞死亡的诱导。本研究的目的是阐明AG1478对三种子宫内膜癌细胞系和两种卵巢癌细胞系的作用，并与正常人类子宫内膜上皮细胞进行比较。细胞分别用不同浓度的AG1478单独处理，或与化疗药物顺铂或紫杉醇联合处理，研究AG1478对细胞生长、细胞周期和细胞凋亡的影响。3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐检测显示，所有癌细胞系对AG1478的生长抑制作用均敏感。与在子宫内膜癌和卵巢癌细胞中诱导生长抑制的相同剂量相比，正常子宫内膜上皮细胞在用AG1478处理后仍保持活力。AG1478与细胞生长抑制剂联合使用可获得协同抗肿瘤作用。细胞周期分析表明，接触这些药物可降低细胞周期中S期细胞的比例，并增加亚G0/G1期细胞的比例。通过膜联蛋白V对外化磷脂酰丝氨酸的染色以及线粒体跨膜电位的丧失，证实了细胞凋亡的诱导。这些结果表明，AG1478单独或与化疗药物联合使用可能是治疗子宫内膜癌和卵巢癌的一种新的治疗选择。
