Antiproliferation in human EA.hy926 endothelial cells and inhibition of VEGF expression in PC-3 cells by topotecan.
Antiproliferation in human EA.hy926 endothelial cells and inhibition of VEGF expression in PC-3 cells by topotecan.
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托泊替康抗人 EA.hy926 内皮细胞增殖并抑制 PC-3 细胞中 VEGF 表达。
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2007-07
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拓扑异构酶I抑制剂拓扑替康（topotecan，TPT）在动物模型和人类肿瘤中均表现出较高的抗癌疗效。这种现象与TPT诱导的肿瘤血管生成抑制有关，但其潜在机制尚不清楚。本研究采用鸡胚绒毛尿囊膜（CAM）法，观察了TPT（1-10 μ M）对血管生成的抑制作用。TPT对人EA.hy926内皮细胞的增殖显示出强抑制活性，IC 50值为0.13 μ M（MTT测定），低于大多数敏感癌细胞系的IC 50值（IC 50范围，0.17 μ M至5.1 μ M）。TPT可诱导EA.hy926细胞发生凋亡，0.05 μ M-5.0 μ M浓度的TPT诱导的凋亡细胞百分率为17.9%-52.3%。AO/EB染色也观察到类似的结果。流式细胞仪检测也显示，不同浓度的TPT诱导的细胞周期紊乱的EA. hy 926细胞。Western blotting结果显示，TPT可明显上调EA.hy926细胞p53蛋白表达，下调ERK蛋白表达。TPT可抑制PC-3细胞缺氧时VEGF的表达。TPT抑制血管内皮细胞增殖、下调肿瘤细胞VEGF表达可能参与了其抗血管生成的作用机制。
Protracted administration of topotecan (TPT), a topoisomerase I inhibitor, exhibited high anticancer efficacy both in animal models and human cancers. This phenomenon is related to the TPT-induced inhibition of angiogenesis in tumor, but the potential mechanism remains largely unknown. In the present study, we reported that TPT (1-10 microM) could inhibit angiogenesis in a dose-dependent manner in Chick embryo chorioallantoic membrane (CAM) assay. TPT showed strong inhibitory activity against proliferation on human EA.hy926 endothelial cells with an IC50 value of 0.13 microM (MTT assay), lower than that of most sensitive cancer cell lines (IC50 range, 0.17 microM to 5.1 microM). TPT could induce EA.hy926 cells undergoing apoptosis, and the percentage of apoptotic cells induced by TPT (0.05 microM-5.0 microM) were 17.9%-52.3%. The similar results were observed with AO/EB staining. Flow cytometry assay also revealed that various concentrations of TPT induced cell cycle disturbance in EA.hy926 cells. Western blotting results showed that TPT caused an obvious increase of p53 expression and a decline of ERK expression in EA.hy926 cells. In addition, the VEGF expression of PC-3 cells is inhibited by TPT in hypoxia. Altogether, inhibiting proliferation of endothelial cells and down-regulating VEGF expression in cancer cells may involve in the antiangiogenesis mechanism of TPT.