Diallyl Disulfide Induces Caspase-Dependent Apoptosis via Mitochondria-Mediated Intrinsic Pathway in B16F-10 Melanoma Cells by Up-Regulating P53, Caspase-3 and Down-Regulating Pro-Inflammatory Cytokines and Nuclear Factor-β-Mediated Bc1-2 Activation
Diallyl Disulfide Induces Caspase-Dependent Apoptosis via Mitochondria-Mediated Intrinsic Pathway in B16F-10 Melanoma Cells by Up-Regulating P53, Caspase-3 and Down-Regulating Pro-Inflammatory Cytokines and Nuclear Factor-β-Mediated Bc1-2 Activation
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DOI：
10.1615/jenvironpatholtoxicoloncol.v29.i2.50
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发表时间：
2010-01-01
影响因子：
2.4
通讯作者：
Kuttan, Girija
中科院分区：
文献类型：
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作者：
Pratheeshkumar, P.;Thejass, P.;Kuttan, Girija
二烯丙基二硫化物(DADS)是从大蒜中提取的一种主要的有机硫化合物，它能抑制各种类型的癌细胞的增殖。在本研究中，我们研究了DADS对B16F-10黑色素瘤细胞的诱导凋亡作用及其对转录因子激活的调节作用。用无毒浓度的DADS处理B16F-10细胞后，可出现凋亡小体，并以剂量依赖的方式诱导DNA片段化。细胞周期分析显示，在DADS处理的细胞中，亚G1峰的出现显著增加。DADS还下调B16F-10黑色素瘤细胞中Bcl2的表达，上调P53、caspase-9和caspase3的表达。本研究还发现，DADS可抑制B16F-10黑色素瘤细胞中核因子xB的p65、p50和c-rel亚单位以及其他转录因子如c-fos、激活的转录因子-2和环磷酸腺苷反应元件结合蛋白的激活和核转位。与对照组相比，DADS处理后的B16F-10转移性黑色素瘤细胞的促炎细胞因子的产生和基因表达下调。DADS通过激活P53和Caspase-3基因的表达，抑制促炎细胞因子和核因子-B介导的Bcl-2活化，通过线粒体介导的内在途径诱导B16F-10黑色素瘤细胞caspase依赖的细胞凋亡。
Diallyl disulfide (DADS) is a major organo-sulfur compound derived from garlic (A ilium sativum), which inhibits the proliferation of various types of cancer cells. In this study we investigated the effect of DADS on the induction of apoptosis, as well as its regulatory effect on the activation of transcription factors in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentrations of DADS resulted in the presence of apoptotic bodies and induced DNA fragmentation in a dose-dependent manner. Cell-cycle analysis revealed that the occurrence of the sub-G1 peak was significantly elevated in DADS-treated cells. DADS treatment also down-reguated Bcl-2 expression and up-regulated p53, caspase-9, and caspase3 expression in B16F-10 melanoma cells. The study also reveals that DADS inhibited the activation and nuclear translocation of p65, p50, and c-Rel subunits of nuclear factor (NF)-xB and other transcription factors, such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein, in B16F-10 melanoma cells The pro-inflammatory cytokine production and gene expression of tumor necrosis factor (TNF)-alpha,interleukin (IL)-1 beta, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were down-regulated in DADS-treated cells compared with control B16F-10 metastatic melanoma cells. DADS induces caspase-dependent apoptosis through a mitochondria-mediated intrinsic pathway in B16F-10 melanoma cells by activating p53 and caspase-3 gene expression and suppressing pro-inflammatory cytokines and NF-B-mediated Bcl-2 activation.