Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Antioxid Redox Signal. 2012 Mar 1;16(5):413-27. doi: 10.1089/ars.2011.3982. Epub 2011 Dec 15.
TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), is a selective killer of tumor cells, although its potential is limited by the development of resistance. In this article, we investigated whether the polyherbal preparation Zyflamend(®) can sensitize tumor cells to TRAIL.
We found that Zyflamend potentiated TRAIL-induced apoptosis in human cancer cells. Zyflamend manifested its effects through several mechanisms. First, it down-regulated the expression of cell survival proteins known to be linked to resistance to TRAIL. Second, Zyflamend up-regulated the expression of pro-apoptotic protein, Bax. Third, Zyflamend up-regulated the expression of death receptors (DRs) for TRAIL. Up-regulation of DRs was critical as gene-silencing of these receptors significantly reduced the effect of Zyflamend on TRAIL-induced apoptosis. The up-regulation of DRs was dependent on CCAAT/enhancer-binding protein-homologous protein (CHOP), as Zyflamend induced CHOP, its gene-silencing abolished the induction of receptors, and mutation of the CHOP binding site on DR5 promoter abolished Zyflamend-mediated DR5 transactivation. Zyflamend mediated its effects through reactive oxygen species (ROS), as ROS quenching reduced its effect. Further, Zyflamend induced DR5 and CHOP and down-regulated the expression of cell survival proteins in nude mice bearing human pancreatic cancer cells.
Zyflamend can sensitize tumor cells to TRAIL through modulation of multiple cell signaling mechanisms that are linked to ROS.
Zyflamend potentiates TRAIL-induced apoptosis through the ROS-CHOP-mediated up-regulation of DRs, increase in pro-apoptotic protein and down-regulation of cell survival proteins.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤细胞的选择性杀伤剂，但其潜力受到耐药性发展的限制。本文研究了复方草药制剂 Zyflamend(®) 是否能使肿瘤细胞对 TRAIL 敏感。
我们发现 Zyflamend 增强了 TRAIL 诱导的人癌细胞凋亡。Zyflamend 通过几种机制发挥作用。首先，它下调了与 TRAIL 耐药相关的已知细胞存活蛋白的表达。其次，Zyflamend 上调了促凋亡蛋白 Bax 的表达。第三，Zyflamend 上调了 TRAIL 的死亡受体（DR）的表达。DR 的上调至关重要，因为这些受体的基因沉默显著降低了 Zyflamend 对 TRAIL 诱导凋亡的影响。DR 的上调依赖于 CCAAT/增强子结合蛋白同源蛋白（CHOP），因为 Zyflamend 诱导 CHOP，其基因沉默消除了受体的诱导，并且 DR5 启动子上的 CHOP 结合位点的突变消除了 Zyflamend 介导的 DR5 反式激活。Zyflamend 通过活性氧（ROS）介导其作用，因为 ROS 淬灭降低了其作用。此外，Zyflamend 在携带人胰腺癌细胞的裸鼠中诱导 DR5 和 CHOP 的表达，并下调细胞存活蛋白的表达。
Zyflamend 可以通过与 ROS 相关的多种细胞信号转导机制来调节肿瘤细胞对 TRAIL 的敏感性。
Zyflamend 通过 ROS-CHOP 介导的 DR 上调、促凋亡蛋白增加和细胞存活蛋白下调来增强 TRAIL 诱导的凋亡。
