Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing
Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing
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DOI：
10.1038/70995
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发表时间：
1999-12
期刊：
影响因子：
82.9
通讯作者：
Michael K. Jones;Hongtao Wang;B. Peskar;E. Levin;R. Itani;I. Sarfeh;A. Tarnawski
中科院分区：
文献类型：
--
作者：
Michael K. Jones;Hongtao Wang;B. Peskar;E. Levin;R. Itani;I. Sarfeh;A. Tarnawski
血管生成，即新毛细血管的形成，不仅对实体瘤的生长和转移至关重要，而且对伤口和溃疡愈合也至关重要，因为如果没有血流的恢复，氧气和营养物质就无法输送到愈合部位1，2。非甾体抗炎药（NSAID），如阿司匹林，吲哚美辛和布洛芬是最广泛使用的药物疼痛，关节炎，心血管疾病，最近，预防结肠癌和阿尔茨海默病3，4，5，6，7。然而，NSAID在约25%的使用者中产生胃十二指肠溃疡（通常伴有出血和/或穿孔），并延迟溃疡愈合8，9，可能是通过阻断环氧合酶（考克斯）-1和考克斯-2合成前列腺素（参考文献10）。假设NSAID的胃肠道副作用是由抑制考克斯-1而不是考克斯-2引起的（参考文献11），促使开发了仅选择性抑制考克斯-2的NSAID（如塞来昔布和罗非昔布）。我们的研究表明，选择性和非选择性NSAID通过直接作用于内皮细胞来抑制血管生成。我们还表明，这种作用涉及抑制有丝分裂原活化蛋白（MAP）激酶（ERK 2）活性，干扰ERK核转位，不依赖于蛋白激酶C，并且具有前列腺素依赖性和前列腺素非依赖性成分。最后，我们表明，考克斯-1和考克斯-2是重要的调节血管生成。这些发现挑战了选择性考克斯-2抑制剂不会影响胃肠道和溃疡/伤口愈合的前提。
Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site 1, 2. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease 3, 4, 5, 6, 7. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing 8, 9, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.