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首页> 外文期刊>Journal of Cellular Physiology >Parthenolide induces caspase-independent and AIF-mediated cell death in human osteosarcoma and melanoma cells
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Parthenolide induces caspase-independent and AIF-mediated cell death in human osteosarcoma and melanoma cells

机译：Parthenolide诱发caspase-independent和人类骨肉瘤和AIF-mediated细胞死亡黑色素瘤细胞

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摘要

The mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. This article shows that parthenolide stimulates in human osteosarcoma MG63 and melanoma SK-MEL-28 cells a mechanism of cell death, which is not prevented by z-VAD-fmk and other caspase inhibitors. In particular treatment with parthenolide rapidly stimulated (1-2h) reactive oxygen species (ROS) generation by inducing activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and NADPH oxidase. This event caused depletion of thiol groups and glutathione, NF-??B inhibition, c-Jun N-terminal kinase (JNK) activation, cell detachment from the matrix, and cellular shrinkage. The increase of ROS generation together with the mitochondrial accumulation of Ca2+ also favored dissipation of ????m, which seemed primarily determined by permeability transition pore opening, since ????m loss was partially prevented by the inhibitor cyclosporin A. Staining with Hoechst 33342 revealed in most cells, at 3-5h of treatment, chromatin condensation, and fragmentation, while only few cells were propidium iodide (PI)-positive. In addition, at this stage apoptosis inducing factor (AIF) translocated to the nucleus and co-localized with areas of condensed chromatin. Prolonging the treatment (5-15h) ATP content declined while PI-positive cells strongly augmented, denouncing the increase of necrotic effects. All these effects were prevented by N-acetylcysteine, while caspase inhibitors were ineffective. We suggest that AIF exerts a crucial role in parthenolide action. In accordance, down-regulation of AIF markedly inhibited parthenolide effect on the production of cells with apoptotic or necrotic signs. Taken together our results demonstrate that parthenolide causes in the two cell lines a caspase-independent cell death, which is mediated by AIF. J. Cell. Physiol. ? 2012 Wiley Periodicals, Inc.
机译：细胞毒性效应产生的机理parthenolide在肿瘤细胞并不清楚今天的定义。parthenolide刺激人类骨肉瘤MG63细胞和黑色素瘤SK-MEL-28机制细胞死亡,这不是由z-VAD-fmk阻止和其他的半胱天冬酶抑制剂。治疗parthenolide迅速刺激(1-2h)活性氧(ROS)生成细胞外的诱导激活signal-regulated激酶1/2 (ERK 1/2)和NADPH氧化酶。组织和谷胱甘肽,NF - ? ?氨基端激酶(物)激活,细胞超然的矩阵,和细胞收缩。在线粒体的积累Ca2 +也青睐耗散? ?似乎主要取决于渗透率过渡毛孔开放,自? ?部分由抑制剂环孢菌素预防答:染色与赫斯特33342年显示在大多数细胞,在治疗3-5h,染色质凝结和分裂,而只有几个细胞被propidium碘(π)阳性。另外,在这个阶段细胞凋亡诱导因素(AIF)转移到细胞核硝唑与凝聚染色质的领域。延长治疗(5-15h) ATP含量拒绝而PI-positive细胞强烈增强,谴责坏死的增加效果。n -乙酰半胱氨酸常在半胱天冬酶抑制剂无效的。在parthenolide行动中的作用。如果下调明显抑制parthenolide影响细胞的生产与凋亡或坏死的迹象。我们的研究结果表明,parthenolide原因在这两个细胞系caspase-independent细胞死亡,如果介导的。杂志。

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