Molecular characterization of cytotoxic and resistance mechanisms induced by NCX 4040, a novel NO-NSAID, in pancreatic cancer cell lines
Molecular characterization of cytotoxic and resistance mechanisms induced by NCX 4040, a novel NO-NSAID, in pancreatic cancer cell lines
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DOI：
10.1007/s10495-006-6986-x
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发表时间：
2006-08-01
期刊：
影响因子：
7.2
通讯作者：
Zoli, Wainer
中科院分区：
文献类型：
--
作者：
Rosetti, Marco;Tesei, Anna;Zoli, Wainer
尽管非类固醇抗炎药(NSAIDs)已被证明是有效的化学预防药物，但重要的副作用限制了它们的临床应用。一氧化氮供体非甾体抗炎药(NO-NSAIDs)是一类很有前途的新型药物，已被发现比经典的非甾体抗炎药具有更强的活性。本研究探讨了非供体阿司匹林衍生物NCX 4040对三种人胰腺癌细胞株(Capan-2、MIA Paca-2和T3M4)的作用。将NCX 4040与NCX 4016(NCX 4040的NO2位置异构体)、SNAP(标准NO释放分子)、NCX 4042(NCX 4040的去硝基类似物)和阿司匹林的活性进行比较。NCX 4040在所有细胞系中都显示出显著的杀细胞活性，在10 mU M时已在Capan-2细胞系中诱导了显著比例的凋亡细胞。本研究重点研究了NCX 4040的敏感性和耐药性的生物学机制，强调该药的细胞毒作用可能是由于Bax的高表达，其转位到线粒体，细胞色素C的释放，以及caspase-9和caspase-3的激活，总体上是以不依赖于p53的方式实现的。此外，在实验模型中使用特定的COX-2抑制剂(NS398)表明COX-2的高表达可以部分解释NCX4040的耐药机制。
Although non steroidal antiinflammatory drugs (NSAIDs) have been shown to be effective as chemopreventive agents, important side-effects limit their clinical use. A promising novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), has been found to be more active than classical NSAIDs. This study explored the effect of the NO-donating aspirin derivative, NCX 4040, on three human pancreatic adenocarcinoma cell lines (Capan-2, MIA PaCa-2 and T3M4). NCX 4040 activity was compared with that of NCX 4016 (an NO2-positional isomer of NCX 4040), SNAP (a standard NO-releasing molecule), NCX 4042 (denitrated analog of NCX 4040), and aspirin. NCX 4040 showed a striking cytocidal activity in all cell lines, already inducing significant percentages of apoptotic cells at 10 mu M in Capan-2 cell lines. This study focused on the biological mechanisms of sensitivity and resistance to NCX 4040, highlighting that the cytotoxic action of this drug may be due to the hyperexpression of Bax, its translocation to the mitochondria, the release of Cytochrome C, and the activation of caspases-9 and -3, overall in a p53-independent manner. Moreover, the use of a specific COX-2 inhibitor (NS 398) in the experimental models showed that COX-2 hyperexpression could partially explain the resistance mechanisms to NCX 4040.