Cell death after co-administration of cisplatin and ethacrynic acid
Cell death after co-administration of cisplatin and ethacrynic acid
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DOI：
10.1016/j.heares.2006.07.015
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发表时间：
2007-04-01
期刊：
影响因子：
2.8
通讯作者：
Salvi, Richard
中科院分区：
文献类型：
--
作者：
Ding, Dalian;Jiang, Haiyan;Salvi, Richard
依他尼酸 (EA) 显着增强顺铂的耳毒性作用。为了深入了解 Cis/EA 耳毒性的机制，用几种细胞凋亡标记物标记耳蜗。 Cis/EA 治疗造成广泛的外毛细胞 (OHC) 和内毛细胞 (IHC) 损伤； OHC 损伤从耳蜗基部向顶端逐渐减少，而 IHC 损伤沿耳蜗长度相对恒定 (25-60%)。碘化丙啶标记的 OHC 细胞核在治疗后 6 小时出现相对正常，在治疗后 12 小时浓缩和破碎，并且在治疗后 48 小时经常缺失。治疗后 6 小时，OHC 中存在与膜死亡受体相关的起始 caspase 8 和 TRADD（一种招募 caspase 8 的蛋白质）。 Caspase 8 标记从 6 It 增加到 24 It，但在处理后 48 小时基本消失。位于 caspase 8 下游的刽子手 caspase 3 和 caspase 6 在处理后 12-24 小时在 OHC 中表达。与线粒体损伤相关的起始 caspase 9 在治疗后 48 小时仅以低水平表达。这些结果表明，Cis/EA 诱导的程序性细胞死亡的快速发生是由与 TRADD 和 caspase 8 相关的膜死亡受体启动的。(C) 2006 Elsevier B.V. 保留所有权利。
Ethacrynic acid (EA) significantly enhances the ototoxic effects of cisplatin. To gain insights into the mechanisms underlying Cis/EA ototoxicity, cochleas were labeled with several apoptotic markers. Cis/EA treatment caused extensive outer hair cell (OHC) and inner hair cell (IHC) damage; OHC lesions decreased from the base towards apex of the cochlea whereas the IHC lesion was relatively constant (25-60%) along the length of the cochlea. Propidium iodide labeled OHC nuclei appeared relatively normal at 6 h post-treatment, were condensed and fragmented at 12 h post-treatment and were frequently missing 48 h post-treatment. Initiator caspase 8, associated with membrane death receptors, and TRADD, a protein that recruits caspase 8, were present in OHC at 6 h post-treatment. Caspase 8 labeling increased from 6 to 24 It, but was largely absent at 48 h post-treatment. Executioner caspase 3 and caspase 6, which lie downstream of caspase 8, were expressed in OHC 12-24 h post-treatment. Initiator caspase 9, associated with mitochondrial damage, was only expressed at low levels at 48 h post-treatment. These results suggest that the rapid onset of Cis/EA induced programmed cell death is initiated by membrane death receptors associated with TRADD and caspase 8. (C) 2006 Elsevier B.V. All rights reserved.