Modulation of tumor necrosis factor-mediated cell death by fullerenes
Modulation of tumor necrosis factor-mediated cell death by fullerenes
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DOI：
10.1007/s11095-007-9486-y
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发表时间：
2008-06-01
影响因子：
3.7
通讯作者：
Trajkovic, Vladimir
中科院分区：
文献类型：
--
作者：
Harhaji, Ljubica;Isakovic, Aleksandra;Trajkovic, Vladimir
目的.通过使用四氢呋喃（THF/nC（60/70））和多羟基化C-60/70 [C-60/70（OH）（n）]的溶剂交换方法制备的富勒烯（C-60/C-70混合物-C-60/70）纳米晶体悬浮液比较它们调节促炎细胞因子肿瘤坏死因子（TNT）的细胞毒性的能力。用结晶紫法检测TNF对L929纤维肉瘤细胞的杀伤作用。采用流式细胞术检测细胞凋亡/坏死、活性氧产生、线粒体去极化和caspase活性。THF/nC（60/70）增强TNF的细胞毒性，而C-60/70（OH）（n）降低TNF的细胞毒性。THF/nC（60/70）或C-60/70（OH）（n）分别增加或减少经历凋亡/坏死的细胞的数量，以及显示caspase家族的凋亡诱导酶活化的细胞的数量。抗氧化剂N-乙酰半胱氨酸和线粒体通透性转换抑制剂环孢菌素A各自部分阻断TNF的细胞毒性作用，表明TNF细胞毒性中涉及氧化应激和线粒体功能障碍。相应地，THF/nC（60/70）或C-60/70（OH）（n）分别增强或抑制TNF触发的氧化应激和线粒体去极化。不同富勒烯制剂调节TNF诱导的氧化应激和随后的细胞死亡的能力表明它们在基于TNF的癌症治疗或预防TNF依赖性组织损伤中的潜在价值。
Purpose. The fullerene (C-60/C-70 mixture-C-60/70) nanocrystalline suspension prepared by solvent exchange method using tetrahydrofyran (THF/nC(60/70)) and polyhydroxylated C-60/70 [C-60/70(OH)(n)] were compared for their ability to modulate cytotoxicity of the proinflammatory cytokine tumor necrosis factor (TNT).Materials and Methods. TNF-induced cytotoxicity was assessed in L929 fibrosarcoma cells by crystal violet assay. The type of cell death (apoptosis/necrosis), production of reactive oxygen species, mitochondrial depolarization and caspase activation were determined by flow cytometry using the appropriate reporter dyes.Results. THF/nC(60/70) augmented, while C-60/70(OH)(n) reduced the cytotoxicity of TNF. The numbers of cells undergoing apoptosis/necrosis, as well as of those displaying the activation of apoptosis-inducing enzymes of caspase family, were respectively increased or reduced by THF/nC(60/70) or C-60/70(OH)(n). The antioxidant N-acetylcysteine and mitochondrial permeability transition inhibitor cyclosporin A each partly blocked the cytotoxic action of TNF, indicating the involvement of oxidative stress and mitochondrial dysfunction in the TNF cytotoxicity. Accordingly, THF/nC(60/70) or C-60/70(OH)(n) potentiated or suppressed, respectively, TNF-triggered oxidative stress and mitochondrial depolarization.Conclusion. The ability of different fullerene preparations to modulate TNF-induced oxidative stress and subsequent cell death suggests their potential value in the TNF-based cancer therapy or prevention of TNF-dependent tissue damage.