Hydroxamate衍生物WMJ-S-001抑制血管新生之分子作用機轉探討

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题名:	Hydroxamate衍生物WMJ-S-001抑制血管新生之分子作用機轉探討 Anti-angiogenic mechanisms of WMJ-S-001, a novel aliphatic hydroxamate
作者:	邱珮婷 Chiu, Pei-Ting
贡献者:	醫學科學研究所許銘仁
关键词:	血管新生 hydroxamate;anti-angiogenesis
日期:	2014-07-04
上传时间:	2019-09-03 12:21:10 (UTC+8)
摘要:	造成癌症病患死亡主要的原因是由於腫瘤細胞的轉移，然而血管新生作用為腫瘤侵襲及轉移主要途徑之一，因此被視為干擾腫瘤生成的治療標的。Hydroxamates由於其具有廣泛的生物及藥理學特性已在現今發展藥物開發領域中引起注意，為了開發出新穎的抑制劑來壓制血管新生及腫瘤生長，我們利用抗血管新生的活性篩選出一種新穎的aliphatic hydroxamate類的藥物為WMJ-S-001，而我們的研究結果發現，在人類臍帶靜脈血管內皮細胞中，WMJ-S-001可以抑制由血管內皮生長因子 (vascular endothelial growth factor ,VEGF)所誘發的細胞增生、遷移以及內皮血管生成等作用，且在ex vivo實驗中，WMJ-S-001會去降低由血管內皮生長因子所誘發從主動脈環所生長出來的出芽作用，以及在in vivo實驗中，WMJ-S-001也會減少由血管內皮生長因子或是HCT116大腸直腸癌細胞所誘發血管新生作用；此外在人類臍帶靜脈血管內皮細胞中，WMJ-S-001亦會抑制血管內皮生長因子誘導之血管內皮生長因子受體-2(VEGF receptor2, VEGFR2)、Src、focal adhesion kinase (FAK)、Akt 及extracellular signal-regulated kinase (ERK)的磷酸化作用。而也發現WMJ-S-001去抑制由血管內皮生長因子所誘發的VEGFR2磷酸化作用、細胞增生及微管柱形成作用可被Src homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP) -1(SHP-1)的抑制作用回復，並且WMJ-S-001也會去增加蛋白磷酸分解酶SHP-1活性，然而WMJ-S-001也會誘發p53蛋白的磷酸化作用及乙醯化作用進而導致p21表現及降低survivin的表現，最終造成細胞凋亡，根據上述實驗結果顯示WMJ-S-001可經由調節血管內皮細胞重新塑造進而導致腫瘤血管新生作用的抑制。希望藉由此論文完成可更瞭解WMJ-S-001之抗血管新生的作用機轉，並且也期許WMJ-S-001或其衍生物在未來對於發展治療癌症轉移之標的策略選擇能有所幫助。 The metastatic spread of tumor cells is the leading cause of death for cancer patients. Angiogenesis, one of the major routes for tumor invasion and metastasis, thus represents a rational target for therapeutic intervention. Recent development in drug discovery has highlighted the diverse biological and pharmacological properties of hydroxamate, a key pharmacophore. In this study, we explored and characterized the anti-angiogenic activities of a novel aliphatic hydroxamate, WMJ-S-001, in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. WMJ-S-001 inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation of human umbilical endothelial cells (HUVECs). WMJ-S-001 also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced VEGF- and HCT116 colorectal cancer cells-induced angiogenesis in vivo. In addition, WMJ-S-001 inhibited the phosphorylations of VEGFR2, Src, FAK, Akt and ERK in VEGF-stimulated HUVECs. Inhibition of SHP-1 restored WMJ-S-001 attenuation of VEGFR2 phosphorylation, cell proliferation and tube formation in VEGF-stimulated HUVECs. WMJ-S-001 also caused an increase in SHP-1 phosphatase activity. Furthermore, WMJ-S-001 also induce p53 phosphorylation and acetylation, leading to apoptosis. These results are associated with the modulation of protein levels of p21 and survivin. Taken together, our findings suggested that WMJ-S-001 may modulate vascular endothelial cell remodeling to inhibit tumor angiogenesis. Understanding the anti-angiogenic mechanisms of WMJ-S-001 will aid in future development of selective-targeting strategies for WMJ-S-001 or its derivatives in the treatment of cancer metastasis.
描述:	碩士指導教授-許銘仁委員-陳彥州委員-陳明仁
数据类型:	thesis
显示于类别:	[醫學科學研究所] 博碩士論文

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