Department of Biophysics, Panjab University, Chandigarh 160014, India.
Biomed Pharmacother. 2012 Jul;66(5):354-67. doi: 10.1016/j.biopha.2012.01.004. Epub 2012 Feb 17.
Angiogenesis refers to the generation of new blood vasculature from the nearby pre-existing one and is regulated by a balance between the pro- and anti-angiogenic factors. During carcinogenesis, pro-angiogenic factors dominate and initialize the growth of new blood capillaries to provide nutrition, growth factors and overcome hypoxia inside the tumor microenvironment. In the present study, we have observed the role of Phosphatidylinositol-3-kinase (PI3-K)/Phophatase and tensin homolog deleted on chromosome ten (PTEN)/Akt (Protein kinase B) pathway and canonical Wnt/β-catenin downstream signaling in the regulation of various pro-angiogenic molecules including the vascular endocrine growth factor-A (VEGF-A), matix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS) and chemokines for the progression of experimental colorectal cancer with 1,2-dimethylhydrazine dihydrochloride (DMH) and anti-angiogenic effects of two non-steroidal anti-inflammatory drugs (NSAIDs) viz. Sulindac and Celecoxib. Morphological and histopathological studies were performed to analyze the tumorigenic modifications while flow cytometry for the relative quantification of apoptotic events. Transcriptional and translational modifications of biomolecules were analyzed via Reverse Transcriptase-and quantitative Real Time PCR, Western immoblotting and immunoflurescence, respectively. In vitro phosphorylation, gelatin zymography and nitric oxide (NO) assay were performed to observe the activation states of Akt, MMPs and iNOS enzyme, respectively. Dysregultion in Akt activation, and thereby, aberrant signaling of β-catenin along with the production of NO could positively regulate tumor angiogenesis. NSAIDs can overcome these carcinogenic effects by controlling various key check points including higher PTEN and glycogen synthase kinase-3β (GSK-3β) expression and repressing Akt, MMPs and iNOS activation while inducing apoptosis among the cancer cells.
血管生成是指从附近的预先存在的血管生成新的血管，由促血管生成和抗血管生成因子之间的平衡调节。在癌变过程中，促血管生成因子占主导地位，并启动新的毛细血管生长，为肿瘤微环境内提供营养、生长因子并克服缺氧。在本研究中，我们观察了磷脂酰肌醇-3-激酶（PI3-K）/磷酸酶和张力蛋白同源物缺失于染色体 10（PTEN）/Akt（蛋白激酶 B）通路和经典 Wnt/β-连环蛋白下游信号在调节各种促血管生成分子中的作用，包括血管内分泌生长因子-A（VEGF-A）、基质金属蛋白酶（MMPs）、诱导型一氧化氮合酶（iNOS）和趋化因子，用于 1,2-二甲基肼二盐酸盐（DMH）诱导的实验性结直肠癌的进展和两种非甾体抗炎药（NSAIDs）的抗血管生成作用，即舒林酸和塞来昔布。进行形态学和组织病理学研究以分析肿瘤发生的变化，同时进行流式细胞术以相对定量分析凋亡事件。通过逆转录酶和定量实时 PCR、Western 免疫印迹和免疫荧光分别分析生物分子的转录和翻译修饰。进行体外磷酸化、明胶酶谱和一氧化氮（NO）测定，以分别观察 Akt、MMPs 和 iNOS 酶的激活状态。Akt 激活失调，从而导致β-连环蛋白信号异常以及 NO 的产生，可正向调节肿瘤血管生成。NSAIDs 可以通过控制包括更高的 PTEN 和糖原合酶激酶-3β（GSK-3β）表达以及抑制 Akt、MMPs 和 iNOS 激活，同时诱导癌细胞凋亡等各种关键检查点来克服这些致癌作用。
