(-)-Oleocanthal as a c-Met Inhibitor for the Control of Metastatic Breast and Prostate Cancers
(-)-Oleocanthal as a c-Met Inhibitor for the Control of Metastatic Breast and Prostate Cancers
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DOI：
10.1055/s-0030-1270724
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发表时间：
2011-07-01
期刊：
影响因子：
2.7
通讯作者：
El Sayed, Khalid A.
中科院分区：
文献类型：
--
作者：
Elnagar, Ahmed Y.;Sylvester, Paul W.;El Sayed, Khalid A.
原癌基因受体酪氨酸激酶c-Met编码肝细胞生长因子（HGF）的高亲和力受体。HGF-c-Met通路的失调在许多肿瘤中起着重要的致瘤作用。c-Met过表达是一些移行细胞癌的预后指标。特级初榨橄榄油（EVOO）提供多种有益的微量酚类化合物。（-）-油烛醛(1)是从EVOO中分离出来的一种天然存在的次要环烯醚萜类化合物，通过抑制COX-1和COX-2的能力显示出强大的抗炎活性。它改变了神经毒性蛋白质的结构，这种蛋白质被认为会导致阿尔茨海默病的衰弱效应。计算机辅助分子设计（CAMD）将1确定为潜在的虚拟c-Met抑制剂hit。油橄榄素分别抑制人乳腺和前列腺上皮细胞MCF7、MDA-MB-231和PC-3的增殖、迁移和侵袭，IC50范围为10-20 μ M；通过下调内皮细胞集落形成细胞中微血管密度标记CD31的表达，显示出抗血管生成活性，IC50范围为4.4 μ M。其IC50值为4.8 μ M.(-)-油酸和EVOO在控制c- met依赖性恶性肿瘤方面具有潜在的治疗作用。
The proto-oncogene receptor tyrosine kinase c-Met encodes the high-affinity receptor for hepatocyte growth factor (HGF). Dysregulation of the HGF-c-Met pathway plays a significant oncogenic role in many tumors. Overexpression of c-Met is a prognostic indicator for some transitional cell carcinomas. Extra-virgin olive oil (EVOO) provides a variety of minor phenolic compounds with beneficial properties. (-)-Oleocanthal (1) is a naturally occurring minor secoiridoid isolated from EVOO, which showed potent anti-inflammatory activity via its ability to inhibit COX-1 and COX-2. It altered the structure of neurotoxic proteins believed to contribute to the debilitating effects of Alzheimer's disease. Computer-Assisted Molecular Design (CAMD) identified 1 as a potential virtual c-Met inhibitor hit. Oleocanthal inhibited the proliferation, migration, and invasion of the epithelial human breast and prostate cancer cell lines MCF7, MDA-MB-231, and PC-3, respectively, with an IC50 range of 10-20 mu M, and demonstrated anti-angiogenic activity via downregulating the expression of the microvessel density marker CD31 in endothelial colony forming cells with an IC50 of 4.4 mu M. It inhibited the phosphorylation of c-Met kinase in vitro in the Z'-LYTE (TM) assay, with an IC50 value of 4.8 mu M. (-)-Oleocanthal and EVOO can have potential therapeutic use for the control of c-Met-dependent malignancies.