Induction of death receptor ligand-mediated apoptosis in epithelial ovarian carcinoma: The search for sensitizing agents
Induction of death receptor ligand-mediated apoptosis in epithelial ovarian carcinoma: The search for sensitizing agents
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DOI：
10.1016/j.ygyno.2009.09.007
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发表时间：
2009-12-01
影响因子：
4.7
通讯作者：
Mangiaracina, Doris
中科院分区：
文献类型：
--
作者：
Moxley, Katherine Marie;Chengedza, Shylet;Mangiaracina, Doris
客观的。旨在评估顺铂、紫杉醇和柔性杂芳香族化合物 (Flex-Het) 化合物 (SHetA2) 使卵巢癌细胞对死亡受体配体、肿瘤坏死因子 α (TNF α) 和 TNF 相关凋亡诱导配体 (TRAIL) 诱导的外源性凋亡途径敏感的能力。研究设计。通过细胞毒性测定、膜联蛋白-V 的流式细胞术分析、碘化丙啶染色以及 caspase 8 和 3 激活的蛋白质印迹分析，测量了 TNF α、TRAIL、顺铂、紫杉醇和 SHetA2 的各种组合对两种已建立的卵巢癌细胞系 A2780 和 SK-OV-3 以及正常人原代子宫内膜培养物的活力和凋亡的影响。结果。卵巢癌和正常细胞对TNFa和TRAIL有抵抗力。顺铂和紫杉醇不会增加任一细胞类型对这些药物的敏感性。相反，SHetA2 与 TNF α 或 TRAIL 组合可协同诱导癌细胞凋亡，涉及外源途径 caspase 8 和刽子手 caspase 3 的激活。TRAIL 组合比 TNF α 组合更有效。 SHetA2 作为单一药物或与死亡受体配体联合使用时不会损害正常细胞的活力。结论。 SHetA2（但不是顺铂或紫杉醇）可以克服卵巢癌细胞对 TNF α 和 TRAIL 的耐药性，而不增加正常细胞对这些死亡受体配体的敏感性。 (C) 2009 Elsevier Inc. 保留所有权利。
Objective. To assess the abilities of cisplatin, paclitaxel, and flexible heteroarotinoid (Flex-Het) compound (SHetA2) to sensitize ovarian cancer cells to induction of the extrinsic apoptosis pathway by death receptor ligands, tumor necrosis factor alpha (TNF alpha), and TNF-related apoptosis-inducing ligand (TRAIL).Study design. The effects of various combinations of TNF alpha, TRAIL, cisplatin, paclitaxel, and SHetA2 on viability and apoptosis in two established ovarian cancer cell lines, A2780 and SK-OV-3, and normal human primary endometrial cultures were measured with a cytotoxicity assay, flow cytometric analysis of annexin-V, and propidium iodide staining and Western blot analysis of caspase 8 and 3 activation.Results. Ovarian cancer and normal cells were resistant to TNFa and TRAIL. Cisplatin and paclitaxel did not increase sensitivity to these agents in either cell type. in contrast, combination of SHetA2 with TNF alpha or TRAIL induced a synergistic induction of apoptosis in cancer cells that involved activation of the extrinsic pathway caspase 8 and executioner caspase 3. The TRAIL combination was more potent than the TNF alpha combination. SHetA2 did not harm the viability of normal cells as a single agent or in combination with the death receptor ligands.Conclusions. SHetA2, but not cisplatin or paclitaxel, can overcome resistance of ovarian cancer cells to TNF alpha and TRAIL without increasing sensitivity of normal cells to these death receptor ligands. (C) 2009 Elsevier Inc. All rights reserved.