Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer.
Curcumin: a novel Stat3 pathway inhibitor for chemoprevention of lung cancer.
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DOI：
10.1097/cej.0b013e32834ef194
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Kumar NB
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文献类型：
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作者：
Alexandrow MG;Song LJ;Altiok S;Gray J;Haura EB;Kumar NB
来自独立小组的多项研究发现，近50%的肺癌中存在Stat 3激活的证据，表明该靶点在肺癌亚群中具有功能性作用。基于现有的证据，我们假设生物可利用的姜黄素复合物可能主要通过抑制Stat 3激活来调节肺癌的发生。随着这种植物的安全性得到很好的确立，这些研究的目的是在体外和体内测试我们的假设，努力为在前吸烟者中进行II期化学预防试验的设计提供信息。我们用生物活性姜黄素C3复合物处理非肿瘤来源的正常（但永生化）人支气管上皮细胞（AALE）和肺腺癌来源的细胞（H441）。将每种情况下的异步细胞用姜黄素处理24小时，然后对Stat 3和活化的Stat 3-P进行免疫印迹，其先前信号用于标准化。我们还完成了一项临床前试验，其中12只小鼠被随机分为三组，并接受3天或9天的姜黄素腹腔注射，然后分析肺组织的Stat 3-P变化和姜黄素的生长抑制作用。使用细胞周期蛋白D1和复制解旋酶亚基Mcm 2作为组织增殖能力的替代物来测量生长抑制作用。用姜黄素类化合物进行的体外研究表明，Stat 3在正常支气管上皮细胞和肺癌衍生细胞中的活性对姜黄素暴露敏感。以剂量依赖性方式，姜黄素处理导致Stat 3磷酸化的显著抑制和两种细胞类型的增殖能力的降低。在啮齿动物模型的临床前试验中，姜黄素降低了体内小鼠肺组织中的Stat 3-P和增殖标志物CycD 1和Mcm 2。这些培养和临床前研究表明，Stat 3通路的活性可以通过姜黄素治疗来抑制，伴随着细胞增殖的减少，支持我们的假设，即Stat 3通路的抑制代表姜黄素增强其对支气管上皮的作用的至少一种重要机制。这些数据为姜黄素作为一种有前途的化学预防剂在高危人群如前吸烟者中的应用提供了理论基础。
Multiple studies from independent groups find evidence for Stat3 activation in nearly 50% of lung cancers suggesting a functional role for this target in subsets of lung cancer. Based on the existing evidence we hypothesized that bioavailable curcuminoid complex may modulate lung carcinogenesis, primarily by inhibiting Stat3 activation. With the safety of this botanical well established, the objective of these studies is to test our hypothesis in vitro and in vivo in an effort to inform the design of a phase II chemoprevention trial in former smokers. We treated non-tumor derived, normal (but immortalized) human bronchial epithelial cells (AALE) and lung adenocarcinoma derived cells (H441) with bioactive Curcumin C3 Complex. Asynchronous cells in each case were treated with curcumin for 24 hrs, followed by immunoblotting for Stat3 and activated Stat3-P, prior signal of which was used for normalization. We also completed a preclinical trial in which 12 mice were randomly divided into three groups and subjected to 3 days or 9 days of curcumin i.p. injections, followed by analysis of lung tissues for Stat3-P changes and growth suppressive effects of the curcumin. The growth suppressive effects were measured using Cyclin D1 and the replicative helicase subunit, Mcm2, as surrogates for the proliferative capacity of the tissues. in vitro studies with curcuminoid complex demonstrated that the activity of Stat3 in both normal bronchoepithelial cells and lung cancer derived cells is sensitive to curcumin exposure. In a dose-dependent manner, curcumin treatment resulted in significant suppression of Stat3 phosphorylation and reduction in the proliferative capacity of both cell types. In the preclinical trial with rodent models, curcumin reduced Stat3-P and the proliferative markers CycD1 and Mcm2 in mice lung tissues in vivo. These culture and preclinical studies indicate that the activity of the Stat3 pathway can be suppressed by curcumin treatment, concomitant with a reduction in cell proliferation, supporting our hypothesis that inhibition of the Stat3 pathway represents at least one important mechanism by which curcumin elicits its effects on the bronchoepithelium. These data provide a rationale for the use of curcumin as a promising chemopreventive agent in high risk populations such as former smokers.