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首页> 外文期刊>Molecular cancer therapeutics >Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins.
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Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins.

机译：大蒜素通过调节死亡受体和抗凋亡蛋白来增强TRAIL诱导的凋亡。

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Whether garcinol, the active component of Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptor 4 (DR4) and DR5. Garcinol neither induced the receptors on normal cells nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induced bid cleavage, bax, and cytochrome c release. Induction of death receptors by garcinol was found to be independent of modulation of CCAAT/enhancer-binding protein-homologous protein, p53, bax, extracellular signal-regulated kinase, or c-Jun-NH(2)-kinase. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as induction of both death receptors, modulation of antiapoptotic and proapoptotic proteins, and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells into TRAIL-sensitive cells. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins. Mol Cancer Ther; 9(4); 856-68. (c)2010 AACR.
机译：研究了藤黄的活性成分藤黄酚是否可以调节癌细胞对TRAIL的敏感性，TRAIL是目前处于II期临床试验的一种细胞因子。我们发现，如细胞内酯酶活性，DNA链断裂，膜磷脂磷脂酰丝氨酸膜的蓄积，线粒体活性以及caspase-8，-9和-3的活化所表明的，藤黄酚可增强TRAIL诱导的癌细胞凋亡。我们发现，藤黄酚与细胞类型无关，可诱导TRAIL受体，死亡受体4（DR4）和DR5。藤黄酚既不会诱导正常细胞上的受体，也不会使其对TRAIL敏感。小干扰RNA删除DR5或DR4显着降低了TRAIL和藤黄酚诱导的细胞凋亡。此外，藤黄酚下调了各种细胞存活蛋白，包括survivin，bcl-2，XIAP和cFLIP，并诱导了双分裂，bax和细胞色素c释放。发现藤黄酚诱导的死亡受体与CCAAT /增强子结合蛋白同源蛋白，p53，bax，细胞外信号调节激酶或c-Jun-NH（2）激酶的调节无关。牛油酚的作用是通过活性氧的产生来介导的，包括两个死亡受体的诱导，抗凋亡蛋白和促凋亡蛋白的调节以及TRAIL诱导的凋亡的增强，都被N-乙酰基半胱氨酸和谷胱甘肽消除了。有趣的是，藤黄酚还将TRAIL耐药细胞转化为TRAIL敏感细胞。总的来说，我们的结果表明，藤黄酚可以通过上调死亡受体和下调抗凋亡蛋白来增强TRAIL诱导的凋亡。分子癌疗法; 9（4）; 856-68。 （c）2010年美国机管学会（AACR）。

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