Phospho-sulindac (OXT-922) inhibits the growth of human colon cancer cell lines: a redox/polyamine-dependent effect
Phospho-sulindac (OXT-922) inhibits the growth of human colon cancer cell lines: a redox/polyamine-dependent effect
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DOI：
10.1093/carcin/bgq149
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发表时间：
2010-11-01
期刊：
影响因子：
4.7
通讯作者：
Rigas, Basil
中科院分区：
文献类型：
--
作者：
Huang, Liqun;Zhu, Caihua;Rigas, Basil
非甾体抗炎药如舒林酸是有前途的结肠癌化学预防剂，但其弱效力和副作用限制了其用于化学预防和化学治疗。在这里，我们评估了一种新的舒林酸衍生物，磷酸-舒林酸或OXT-922，对人类癌细胞系的生长及其作用机制的影响。OXT-922抑制源自结肠、胰腺和乳腺的人癌细胞系的生长的效力比舒林酸高11至30倍。这种效应是由一个强大的细胞动力学效应介导的。与对照组相比，OXT-922抑制细胞增殖高达67%，诱导细胞凋亡是对照组的4.1倍，并阻断G（1）至S细胞周期的转变。OXT-922抑制细胞周期调节蛋白的水平，包括细胞周期蛋白D-1和D-3以及细胞周期蛋白依赖性激酶（CDK）4和6。响应于OXT-922，细胞内活性氧（ROS）的水平，特别是线粒体O-2（中心点-）的水平显著升高（5.5倍）。ROS破坏线粒体膜电位并引发细胞凋亡，这在很大程度上被抗氧化剂消除。OXT-922抑制核因子-κ B活化并下调硫氧还蛋白-1表达。它还抑制前列腺素E-2的产生并降低环氧合酶-1的表达。与舒林酸相似，OXT-922增强亚精胺/精胺N-1-乙酰转移酶活性，降低细胞多胺含量，并与二氟甲基鸟氨酸协同抑制癌细胞增殖和诱导凋亡。我们的研究结果表明，OXT-922具有良好的抗癌特性，值得进一步评价。
Non-steroidal anti-inflammatory drugs such as sulindac are promising chemoprevention agents against colon cancer, but their weak potency and side effects limit their use for both chemoprevention and chemotherapy. Here, we evaluated the effect of a new sulindac derivative, phospho-sulindac or OXT-922, on the growth of human cancer cell lines and its mechanism of action. OXT-922 inhibited the growth of human cancer cell lines originating from colon, pancreas and breast similar to 11- to 30-fold more potently than sulindac. This effect was mediated by a strong cytokinetic effect. Compared with control, OXT-922 inhibited cell proliferation by up to 67%, induced apoptosis 4.1-fold over control and blocked the G(1) to S cell cycle phase transition. OXT-922 suppressed the levels of cell cycle regulating proteins, including cyclins D-1 and D-3 and Cyclin-dependent kinases (CDK) 4 and 6. The levels of intracellular reactive oxygen species (ROS), especially those of mitochondrial O-2(center dot-), were markedly elevated (5.5-fold) in response to OXT-922. ROS collapsed the mitochondrial membrane potential and triggered apoptosis, which was largely abrogated by antioxidants. OXT-922 suppressed nuclear factor-kappaB activation and downregulated thioredoxin-1 expression. It also suppressed the production of prostaglandin E-2 and decreased cyclooxygenase-1 expression. Similar to sulindac, OXT-922 enhanced spermidine/spermine N-1-acetyltransferase activity, reduced the cellular polyamine content and synergized with difluoromethylornithine to inhibit cancer cell proliferation and induce apoptosis. Our results suggest that OXT-922 possesses promising anticancer properties and deserves further evaluation.