Anti-cancer activity and potential mechanism of a novel aspirin derivative
Anti-cancer activity and potential mechanism of a novel aspirin derivative
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DOI：
10.1016/j.ejphar.2016.07.050
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发表时间：
2016-11-15
影响因子：
5
通讯作者：
Li, Sen
中科院分区：
文献类型：
--
作者：
Zong, Ming;Fan, Dan-Dan;Li, Sen
阿司匹林已被用于许多恶性肿瘤的治疗和化学预防。其抗肿瘤作用机制主要是通过抑制环氧化酶-2（考克斯-2）而实现的。然而，阿司匹林的应用受到其使用所伴随的严重胃粘膜损伤的限制。我们以前报道了一种新的阿司匹林衍生物的制备，我们命名为Ca-Asp，并表明它对大鼠胃粘膜的损伤较小，抑制考克斯-2的表达的程度高于Asp。但Ca-Asp的抗癌作用及其机制尚不清楚。本研究在细胞水平上研究了Ca-Asp的抗癌作用，并与Asp和羟基磷灰石（Hap）进行了比较。结果表明，与用Asp或Hap处理相比，用200-400 μ g/ml Ca-Asp处理SGC-7901细胞（人胃癌细胞系）导致细胞活力的显著降低，并且在更高浓度（500 μ g/ml）下。随后对可能的潜在机制的研究表明，Ca-Asp诱导细胞凋亡，并导致细胞周期停滞在G1期。Ca-Asp还上调caspase-3和p53的水平，下调cyclin D1、NF-κ β、考克斯-2和PGE的水平（2）。此外，Ca-Asp和外源性PGE（2）同时作用于SGC-7901细胞，可降低Ca-Asp对细胞增殖的抑制作用。这些结果表明，Ca-Asp可能是一种潜在的抗癌药物，其抑制PGE（2）的产生可能是其抗癌活性的重要组成部分。(C)© 2016 Elsevier B. V.版权所有。
Aspirin has been used in the treatment and chemoprevention of many malignant cancers. The mechanism of its anti-cancer activity mainly involves the inhibition of cyclooxygenase-2 (COX-2). However, the application of aspirin is limited by the serious gastric mucosal damage that accompanies its usage. We have previously reported the preparation of a novel aspirin derivative that we named Ca-Asp, and showed that it causes less damage to gastric mucosa of rat and inhibits the expression of COX-2 to higher degree than Asp. However, the anti-cancer effect and mechanism of Ca-Asp was not demonstrated. In this study, the anti-cancer effect of Ca-Asp was investigated and compared with those of Asp and Hydroxyapatite (Hap) at the cell level. The results showed that treatment of SGC-7901 cells (human gastric cancer cell line) with 200-400 mu g/ml Ca-Asp resulted in significant reduction in cell viability, compared to treatment with either Asp or Hap, and at a higher concentration (500 mu g/ml). Subsequent investigation into the possible underlying mechanism showed that Ca-Asp induced apoptosis and caused cell cycle arrest at the G1 phase. Ca-Asp also up regulated the levels of caspase-3 and p53, but down regulated the level of cyclin D1, NF-kappa beta, COX-2 and PGE(2). Furthermore, simultaneous treatment of SGC-7901 cells with Ca-Asp and exogenous PGE(2) reduced the anti-proliferative effect of Ca-Asp on the cells. Taken together, the results suggested that Ca-Asp might act as a potential anti-cancer drug, and that its suppression of PGE(2) production might constitute an important part of its anti-cancer activity. (C) 2016 Elsevier B.V. All rights reserved.