Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress
Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress
复制标题
DOI：
10.1073/pnas.0506893102
复制
发表时间：
2005-11-22
影响因子：
11.1
通讯作者：
Rigas, B
中科院分区：
文献类型：
--
作者：
Gao, JJ;Liu, XP;Rigas, B
一氧化氮供体阿司匹林（NO-ASA）是一种很有前途的结肠癌和其他癌症的化学预防剂。它由传统的阿萨组成，其中NO释放部分通过间隔基结合。NO-ASA抑制结肠癌细胞生长的能力比阿萨强几百倍。在Min小鼠中，NO-ASA抑制肠癌发生而不影响细胞增殖。因此，我们研究了NO-ASA最重要的细胞动力学效应是否是诱导细胞凋亡。在确认诱导Min小鼠凋亡后，我们研究了人结肠腺癌细胞的潜在机制。NO-ASA的间隔基与谷胱甘肽形成共轭物，消耗谷胱甘肽储存。这诱导了氧化应激（增加细胞内过氧化物和O-2（.）-水平）通过激活内在凋亡途径导致凋亡。NO-ASA通过诱导β-和γ-连环蛋白裂解破坏粘附连接，导致细胞脱离。NO-ASA通过双重机制抑制Wnt信号传导：在低浓度下，它阻断β-连环蛋白/Tcf复合物的形成（主导机制），在较高浓度下，它还切割β-连环蛋白。这些发现提供了一种有效的化学预防剂的作用机制，强调了这些途径在癌症化学预防背景下调节细胞死亡的重要性，并为开发具有增强的癌细胞生长抑制特性的药物提供了范例。
Nitric oxide-donating aspirin (NO-ASA) is a promising chemoprevention agent against colon cancer and other cancers. It consists of traditional ASA to which a NO-releasing moiety is bound through a spacer. NO-ASA inhibits colon cancer cell growth several hundred times more potently than does ASA. In Min mice, NO-ASA inhibited intestinal carcinogenesis without affecting cell proliferation. Thus, we examined whether NO-ASA's most important cell kinetic effect is the induction of apoptosis. After confirming induction of apoptosis in Min mice, we studied the underlying mechanism in human colon adenocarcinoma cells. NO-ASA's spacer formed a conjugate with glutathione, depleting glutathione stores. This induced oxidative stress (increased intracellular levels of peroxides and O-2(.)-) leads to apoptosis by activating the intrinsic apoptosis pathway. NO-ASA disrupted adherens junctions by inducing cleavage of beta-and gamma-catenin, resulting in cell detachment. NO-ASA inhibited Wnt signaling by a dual mechanism: at low concentrations it blocked the formation of beta-catenin/Tcf complexes (dominant mechanism), and at higher concentrations it also cleaved beta-catenin. These findings provide a mechanism of action by a potent chemopreventive agent, underscore the significance of these pathways in regulating cell death in the context of cancer chemoprevention, and present a paradigm for developing agents with enhanced cancer cell growth inhibitory properties.