Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.
Eur J Pharmacol. 2011 Jan 10;650(1):120-9. doi: 10.1016/j.ejphar.2010.10.005. Epub 2010 Oct 14.
The effect of the natural compound damnacanthal from Morinda citrifolia on SKHep 1 cell growth regulation was investigated. Treatment of SKHep 1 cells with damnacanthal for 24h indicated a dose-dependent antiproliferative activity. Damnacanthal seems to be selective for tumor cell lines, since there is only minimal toxicity against normal hepatocyte cells (FL83B). This is first demonstration that damnacanthal-mediated apoptosis involves the sustained activation of the p38 MAPK pathway, leading to the transcription of the death receptor family genes encoding DR5/TRAIL and TNF-R1/TNF-α genes as well as the p53-regulated Bax gene. The damnacanthal-mediated expression of DR5/TRAIL and TNF-R1/TNF-α results in caspase 8 activation, leading to Bid cleavage. In turn, activated Bid, acting with p53-regulated Bax, leads to cytochrome c released from mitochondria into the cytoplasm. Combined activation of the death receptors and mitochondrial pathways results in activation of the downstream effecter caspase 3, leading to cleavage of PARP. TRAIL- and TNF-α-mediated damnacanthal-induced apoptosis could be suppressed by treatment with caspase inhibitors as well as soluble death receptors Fc:DR5 and Fc:TNF-R1 chimera. Taken together, this study provided first evidence demonstrating that TRAIL-, TNF-α-, and p53-mediated damnacanthal-induced apoptosis require the activation of p38 MAPK and mitochondrion-mediated caspase-dependent pathways.
天然化合物 damnacanthal 来自 Morinda citrifolia 对 SKHep 1 细胞生长调节的影响。用 damnacanthal 处理 SKHep 1 细胞 24 小时表明其具有剂量依赖性的抗增殖活性。Damnacanthal 似乎对肿瘤细胞系具有选择性，因为它对正常肝细胞（FL83B）只有最小的毒性。这是首次证明 damnacanthal 介导的细胞凋亡涉及 p38 MAPK 通路的持续激活，导致编码 DR5/TRAIL 和 TNF-R1/TNF-α基因以及 p53 调节的 Bax 基因的死亡受体家族基因的转录。Damnacanthal 介导的 DR5/TRAIL 和 TNF-R1/TNF-α的表达导致 caspase 8 的激活，导致 Bid 的切割。反过来，激活的 Bid 与 p53 调节的 Bax 一起作用，导致细胞色素 c 从线粒体释放到细胞质中。死亡受体和线粒体途径的联合激活导致下游效应物 caspase 3 的激活，导致 PARP 的切割。用 caspase 抑制剂以及可溶性死亡受体 Fc:DR5 和 Fc:TNF-R1 嵌合体处理可以抑制 TRAIL 和 TNF-α介导的 damnacanthal 诱导的细胞凋亡。总之，这项研究提供了第一个证据，证明 TRAIL、TNF-α 和 p53 介导的 damnacanthal 诱导的细胞凋亡需要 p38 MAPK 和线粒体介导的 caspase 依赖性途径的激活。
