Dobrovolskaia Marina A, Kozlov Serguei V
National Cancer Institute at Frederick, Boyles St., P.O. Box B, Frederick, MD 21702, USA.
Curr Cancer Drug Targets. 2005 Aug;5(5):325-44. doi: 10.2174/1568009054629645.
Chronic inflammation has long been suggested to constitute a risk factor for a variety of epithelial cancers such as malignancies of prostate, cervix, esophagus, stomach, liver, colon, pancreas, and bladder. An inflammatory response is typically accompanied by generation of free radicals, stimulation of cytokines, chemokines, growth and angiogenic factors. Free radicals, capable of both directly damaging DNA and affecting the DNA repair machinery, enhance genetic instability of affected cells, thus contributing to the first stage of neoplastic transformation also known as "initiation". Cytokines and growth factors can further promote tumor growth by stimulating cell proliferation, adhesion, vascularization, and metastatic potential of later stage tumors. Nuclear factor kappa B (NF-kappaB) is a family of ubiquitously expressed transcription factors that are widely believed to trigger both the onset and the resolution of inflammation. NF-kappaB also governs the expression of genes encoding proteins essential in control of stress response, maintenance of intercellular communications, and regulation of cellular proliferation and apoptosis. Recent data have expanded the concept of inflammation as a critical component in carcinogenesis suggesting new anti-inflammatory therapies for a complementary approach in treating a variety of tumor types. These observations highlighted the NF-kappaB pathway as an attractive avenue for drug discovery and development. The present review will outline recent advances in our understanding of NF-kappaB function in the inflammatory processes and its input in tumor initiation/promotion, as well as summarize the development of animal and cell culture models for validating drug candidates with NF-kappaB-modulating activities, and applications of the latter in cancer therapy.
长期以来，慢性炎症一直被认为是多种上皮性癌症的危险因素，如前列腺癌、宫颈癌、食管癌、胃癌、肝癌、结肠癌、胰腺癌和膀胱癌。炎症反应通常伴随着自由基的产生、细胞因子、趋化因子、生长因子和血管生成因子的刺激。自由基既能直接损伤DNA，又能影响DNA修复机制，增强受影响细胞的遗传不稳定性，从而促成肿瘤转化的第一阶段，即“启动”阶段。细胞因子和生长因子可通过刺激后期肿瘤的细胞增殖、黏附、血管生成和转移潜能，进一步促进肿瘤生长。核因子κB（NF-κB）是一类广泛表达的转录因子家族，人们普遍认为它能引发炎症的发生和消退。NF-κB还调控着编码在应激反应控制、细胞间通讯维持以及细胞增殖和凋亡调节中起关键作用的蛋白质的基因表达。最近的数据扩展了炎症作为致癌作用关键组成部分的概念，提示了新的抗炎疗法作为治疗多种肿瘤类型的补充方法。这些观察结果突出了NF-κB信号通路作为药物发现和开发的一个有吸引力的途径。本综述将概述我们对NF-κB在炎症过程中的功能及其在肿瘤起始/促进中的作用的最新认识进展，总结用于验证具有NF-κB调节活性的候选药物的动物和细胞培养模型的开发，以及后者在癌症治疗中的应用。
