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姜黄素类化合物与胚胎癌细胞的结合:还原代谢、诱导细胞凋亡、衰老和抑制细胞增殖。

Curcuminoid binding to embryonal carcinoma cells: reductive metabolism, induction of apoptosis, senescence, and inhibition of cell proliferation.

机构信息

Department of Psychiatry and Behavioral Science, State University of New York at Stony Brook, Stony Brook, New York, United States of America.

出版信息

PLoS One. 2012;7(6):e39568. doi: 10.1371/journal.pone.0039568. Epub 2012 Jun 26.

Abstract

Curcumin preparations typically contain a mixture of polyphenols, collectively referred to as curcuminoids. In addition to the primary component curcumin, they also contain smaller amounts of the co-extracted derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids can be differentially solubilized in serum, which allows for the systematic analysis of concentration-dependent cellular binding, biological effects, and metabolism. Technical grade curcumin was solubilized in fetal calf serum by two alternative methods yielding saturated preparations containing either predominantly curcumin (60%) or bisdemethoxycurcumin (55%). Continual exposure of NT2/D1 cells for 4-6 days to either preparation in cell culture media reduced cell division (1-5 µM), induced senescence (6-7 µM) or comprehensive cell death (8-10 µM) in a concentration-dependent manner. Some of these effects could also be elicited in cells transiently exposed to higher concentrations of curcuminoids (47 µM) for 0.5-4 h. Curcuminoids induced apoptosis by generalized activation of caspases but without nucleosomal fragmentation. The equilibrium binding of serum-solubilized curcuminoids to NT2/D1 cells incubated with increasing amounts of curcuminoid-saturated serum occurred with apparent overall dissociation constants in the 6-10 µM range. However, the presence of excess free serum decreased cellular binding in a hyperbolic manner. Cellular binding was overwhelmingly associated with membrane fractions and bound curcuminoids were metabolized in NT2/D1 cells via a previously unidentified reduction pathway. Both the binding affinities for curcuminoids and their reductive metabolic pathways varied in other cell lines. These results suggest that curcuminoids interact with cellular binding sites, thereby activating signal transduction pathways that initiate a variety of biological responses. The dose-dependent effects of these responses further imply that distinct cellular pathways are sequentially activated and that this activation is dependent on the affinity of curcuminoids for the respective binding sites. Defined serum-solubilized curcuminoids used in cell culture media are thus suitable for further investigating the differential activation of signal transduction pathways.

摘要

姜黄素制剂通常含有多酚的混合物,统称为姜黄素类。除了主要成分姜黄素外,它们还含有较小量的共提取衍生物脱甲氧基姜黄素和双脱甲氧基姜黄素。姜黄素类可以在血清中差异溶解,这允许对浓度依赖性细胞结合、生物效应和代谢进行系统分析。技术级姜黄素通过两种替代方法溶解在胎牛血清中,得到的饱和制剂主要含有姜黄素(60%)或双脱甲氧基姜黄素(55%)。连续暴露于细胞培养基中的任一制剂中,NT2/D1 细胞持续 4-6 天,以浓度依赖的方式减少细胞分裂(1-5μM),诱导衰老(6-7μM)或全面细胞死亡(8-10μM)。这些效应中的一些也可以在短暂暴露于更高浓度姜黄素类(47μM)0.5-4 小时的细胞中引起。姜黄素类通过普遍激活半胱天冬酶诱导细胞凋亡,但没有核小体片段化。与孵育有增加量姜黄素类饱和血清的 NT2/D1 细胞平衡结合的血清可溶解的姜黄素类,其表观总体离解常数在 6-10μM 范围内。然而,过量的游离血清以双曲线方式降低细胞结合。细胞结合主要与膜部分相关,结合的姜黄素类在 NT2/D1 细胞中通过以前未识别的还原途径代谢。姜黄素类的结合亲和力及其还原代谢途径在其他细胞系中均有所不同。这些结果表明,姜黄素类与细胞结合位点相互作用,从而激活启动各种生物反应的信号转导途径。这些反应的剂量依赖性效应进一步表明,不同的细胞途径依次被激活,并且这种激活依赖于姜黄素类对各自结合位点的亲和力。因此,在细胞培养基中使用的定义明确的血清可溶解姜黄素类适用于进一步研究信号转导途径的差异激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3301/3383725/e3c3eb150479/pone.0039568.g001.jpg

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