Specific killing of multiple myeloma cells by (-)-epigaflocatechin-3-gallate extracted from green tea: biologic activity and therapeutic implications
Specific killing of multiple myeloma cells by (-)-epigaflocatechin-3-gallate extracted from green tea: biologic activity and therapeutic implications
复制标题
DOI：
10.1182/blood-2006-05-022814
复制
发表时间：
2006-10-15
期刊：
影响因子：
20.3
通讯作者：
Munshi, Nikhil C.
中科院分区：
文献类型：
--
作者：
Shammas, Masood A.;Neri, Paola;Munshi, Nikhil C.
表没食子儿茶素没食子酸酯（Epigallocatechin-3-gallate，EGCG）是从绿色茶中提取的一种多酚类化合物，是一种具有化学预防和化学治疗作用的抗氧化剂。基于其调节生长因子介导的细胞增殖的能力，我们评估了其在多发性骨髓瘤（MM）中的疗效。EGCG诱导剂量和时间依赖性生长停滞和随后的MM细胞系，包括IL-6依赖性细胞和原代患者细胞的凋亡细胞死亡，对外周血单核细胞（PBMC）和正常成纤维细胞的生长没有显着影响。用EGCG治疗还导致在SCID小鼠中作为肿瘤生长的人骨髓瘤细胞的显著凋亡。EGCG与67-kDa层粘连蛋白相互作用。受体1（LR 1），其在骨髓瘤细胞系和患者样品中相对于正常PBMC显著升高。RNAl介导的LR 1抑制导致骨髓瘤细胞中EGCG诱导的细胞凋亡的消除，表明LR 1在介导MM中的EGCG活性而不影响PBMC中起重要作用。对基因表达谱变化的评估表明，EGCG处理通过诱导死亡相关蛋白激酶2（死亡受体依赖性凋亡的启动子和介质）的表达，激活MM细胞中生长停滞和凋亡的不同途径（Fas配体，Fas和caspase 4），p53样蛋白（p73、p63）、细胞凋亡和NF-κ B激活的阳性调节因子（CARD 10、CARD 14）以及细胞周期蛋白依赖性激酶抑制剂（p16和p18）。蛋白质印迹分析也证实了相关基因在蛋白质水平上的表达。这些数据证明了有效的和特定的抗骨髓瘤活性的表没食子儿茶素没食子酸酯，并提供了基本原理，其临床评价。
Epigallocatechin-3-gallate (EGCG), a polyphenol extracted from green tea, is an antioxidant with chemopreventive and chemotherapeutic actions. Based on its ability to modulate growth factor-mediated cell proliferation, we evaluated its efficacy in multiple myeloma (MM). EGCG induced both dose- and time-dependent growth arrest and subsequent apoptotic cell death in MM cell lines including IL-6-dependent cells and primary patient cells, without significant effect on the growth of peripheral blood mononuclear cells (PBMCs) and normal fibroblasts. Treatment with EGCG also led to significant apoptosis in human myeloma cells grown as tumors in SCID mice. EGCG interacts with the 67-kDa laminin. receptor 1 (LR1), which is significantly elevated in myeloma cell lines and patient samples relative to normal PBMCs. RNAl-mediated inhibition of LR1 resulted in abrogation of EGCG-induced apoptosis in myeloma cells, indicating that LR1 plays an important role in mediating EGCG activity in MM while sparing PBMCs. Evaluation of changes in gene expression profile indicates that EGCG treatment activates distinct pathways of growth arrest and apoptosis in MM cells by inducing the expression of death-associated protein kinase 2, the initiators and mediators of death receptor-dependent apoptosis (Fas ligand, Fas, and caspase 4), p53-like proteins (p73, p63), positive regulators of apoptosis and NF-kappa B activation (CARD10, CARD14), and cyclin-dependent kinase inhibitors (p16 and p18). Expression of related genes at the protein level were also confirmed by Western blot analysis. These data demonstrate potent and specific antimyeloma activity of EGCG and provide the rationale for its clinical evaluation.