Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy.
Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy.
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DOI：
10.2174/138955707780859431
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发表时间：
2007-05
期刊：
影响因子：
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通讯作者：
F. Sarkar;S. Adsule;Yiwei Li;S. Padhye
中科院分区：
文献类型：
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作者：
F. Sarkar;S. Adsule;Yiwei Li;S. Padhye
超过世纪以来，通过抑制脂肪酸环氧合酶（考克斯）来抑制前列腺素生物合成已通过非甾体抗炎药（NSAID）实现，其靶向考克斯-1和考克斯-2，因此可能导致胃肠道（GI）毒性。考克斯-2是一种诱导酶，由多种细胞类型响应多种刺激而产生。最近，考克斯-2的过度表达已被发现在几种类型的人类癌症，如结肠癌，乳腺癌，前列腺癌和胰腺癌，似乎控制许多细胞过程。由于其在致癌、凋亡和血管生成中的作用，它是开发具有选择性的预防和/或治疗人类癌症的新药的极好靶点。选择性考克斯-2抑制剂的开发已被成功记录，并且与常规NSAID相比，其对胃肠道的毒性较小。然而，长期使用考克斯-2选择性抑制剂显示心血管毒性，因此它们用于癌症预防和治疗目前是值得怀疑的，这表明需要进一步开发新的考克斯-2选择性药物。在许多实体瘤中，胰腺癌的预后最差，炎症已被确定为胰腺恶性肿瘤发展的重要因素。多种细胞因子、活性氧（ROS）和炎症途径的介质如核因子-κ B（NF-kappaB）和考克斯-2的活化导致细胞增殖、存活增加和促凋亡途径的抑制，最终导致肿瘤血管生成、侵袭和转移。本文就考克斯-2在胰腺癌发生发展中的作用进行综述，并对炎症与胰腺癌发生发展的相关实验数据进行讨论。此外，我们提供了关于我们对开发用于预防和/或治疗人类癌症特别是胰腺癌的新型考克斯-2靶向剂的知识状态的进一步证据。
For more than a century, inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) has been achieved by non-steroidal anti-inflammatory drugs (NSAIDs), which targets both COX-1 and COX-2 and as such could be responsible for causing gastrointestinal (GI) toxicity. COX-2 is an inducible enzyme produced by many cell types in response to multiple stimuli. Recently, COX-2 over-expression has been found in several types of human cancers such as colon, breast, prostate and pancreas and appears to control many cellular processes. Because of its role in carcinogenesis, apoptosis, and angiogenesis, it is an excellent target for developing new drugs with selectivity for prevention and/or treatment of human cancers. Development of selective COX-2 inhibitors has been successfully documented and as such showed less toxicity to GI tract as compared to conventional NSAIDs. However, the long term use of COX-2 selective inhibitors showed cardiovascular toxicity, and thus their utilization for cancer prevention and therapy is currently questionable, suggesting that further development of novel COX-2 selective agents are needed. Among many solid tumors, pancreatic cancer has the worst prognosis, and inflammation has been identified as a significant factor in the development of pancreatic malignancy. Several cytokines, reactive oxygen species (ROS) and mediators of inflammatory pathway such as activation of nuclear factor-kappaB (NF-kappaB) and COX-2 leads to an increase in cell proliferation, survival, and inhibition of pro-apoptotic pathway, ultimately resulting in tumor angiogenesis, invasion and metastasis. In this brief review, we summarize the role of COX-2 and discuss some of the experimental data linking inflammation with the development of pancreatic cancer. In addition, we provide further evidence regarding the state of our knowledge toward the development of novel COX-2 targeting agents for the prevention and/or treatment of human cancers especially pancreatic cancer.