Pro-apoptotic effect of a nitric oxide-donating NSAID, NCX 4040, on bladder carcinoma cells
Pro-apoptotic effect of a nitric oxide-donating NSAID, NCX 4040, on bladder carcinoma cells
复制标题
DOI：
10.1007/s10495-005-0619-7
复制
发表时间：
2005-10-01
期刊：
影响因子：
7.2
通讯作者：
Zoli, W
中科院分区：
文献类型：
--
作者：
Fabbri, F;Brigliadori, G;Zoli, W
释放一氧化氮的非甾体抗炎药（NO-NSAID）是一类很有前途的化合物，可引起细胞周期紊乱并诱导不同肿瘤细胞系的凋亡。我们研究了最近开发的NO-NSAID（NCX 4040）在膀胱癌细胞系（HT 1376和MCR）中的活性。细胞用不同的药物浓度处理不同的暴露时间。SRB法检测细胞生长抑制和细胞杀伤活性，TUNEL法、ANNEXIN V法和荧光显微镜观察细胞凋亡。为了进一步研究NCX 4040诱导细胞死亡的机制，我们分析了gp-170、caspase表达和线粒体膜电位（Delta psi）去极化。NCX 4040在两种细胞系中均显示出显著的杀细胞活性，在HT 1376和MCR细胞中分别在10 μ M和50 μ M浓度下达到LC 50，暴露仅6小时后进行18小时洗脱。在高达90%的细胞中触发了细胞凋亡，并且在6小时暴露后，与两种细胞系中的活性半胱天冬酶-3表达和Δ psi去极化相关。总之，NCX 4040可能通过膀胱依赖性机制引起细胞凋亡，可以证明是改善膀胱癌治疗的有用药物。
Nitric oxide-releasing non steroidal anti-inflammatory drugs (NO-NSAIDs) are a promising class of compounds that cause cell cycle perturbations and induce apoptosis in cell lines from different tumors. We investigated the activity of a recently developed NO-NSAID (NCX 4040) in bladder cancer cell lines (HT1376 and MCR). Cells were treated with different drug concentrations for different exposure times. Cytostatic and cytocidal activity was tested by SRB assay and apoptosis was evaluated by TUNEL analysis, ANNEXIN V assay and fluorescence microscopy. To further investigate the cell death-inducing mechanisms of NCX 4040, we analyzed gp-170, caspase expression and mitochondrial membrane potential (Delta psi) depolarization. NCX 4040 showed a striking cytocidal activity in both cell lines, reaching LC50 at a 10-mu M and 50-mu M concentrations in HT1376 and in MCR cells, respectively, after an exposure of only 6 h followed by an 18-h washout. Apoptosis was triggered in up to 90% of cells and was associated with active caspase-3 expression and Delta psi depolarization in both cell lines after a 6-h exposure. In conclusion, NCX 4040, which probably causes apoptosis via a mitochondrial-dependent mechanism, could prove to be a useful agent for improving bladder cancer treatment.