HDAC抑制劑抑制腫瘤血管新生作用機轉之探討

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Title:	HDAC抑制劑抑制腫瘤血管新生作用機轉之探討 Inhibitory mechanisms of HDAC inhibitor in tumor angiogenesis
Authors:	Chang, Yi-Fang
Keywords:	血管新生;內皮細胞;羥基醯胺;蛋白p53;血管內皮生長因子;Angiogenesis;Endothelial cells;Hydroxamate;p53;VEGF
Date:	2014-01-12
Issue Date:	2018-11-14 09:54:26 (UTC+8)
Abstract:	血管新生是腫瘤侵襲和轉移的主要路徑，因此血管新生便成為一治療腫瘤轉移的重要標的。最近在藥物的發展上，烴基醯胺衍生物因其具有廣泛之生理和藥理活性而被科學家所重視。在本論文，我們合成並篩選了一長鏈烴基醯胺衍生物WMJ-S-001，同時進一步探討其抗血管新生活性和可能作用機轉。研究結果發現WMJ-S-001會抑制血管內皮細胞生長因子VEGF-A所誘導之血管內皮細胞HUVEC的增生、侵襲和微管柱形成現象。WMJ-S-001也會抑制大鼠主動脈環出芽現象，利用異種移殖動物模式，我們也發現WMJ-S-001會抑制腫瘤血管新生作用。另一方面，WMJ-S-001會抑制VEGF-A所誘導血管內皮細胞膜上受體VEGFR2及其下游訊息分子如Src、 FAK、Akt和ERK的磷酸化， WMJ-S-001也被證實可增加細胞內蛋白磷酸分解酶SHP-1的酵素活性，同時SHP-1抑制劑 NSC-87877則會回復WMJ-S-001所抑制VEGFR2的磷酸化和細胞增生之作用。我們也發現WMJ-S-001會抑制血管內皮細胞週期之進行和誘導細胞凋亡，這些作用伴隨著轉錄因子p53的磷酸化和乙醯化增加和細胞內p21和survivin蛋白濃度的改變。綜而言之，在本論文我們發現長鏈烴基醯胺衍生物WMJ-S-001可以經由抑制VEGFR2訊息路徑和誘導細胞凋亡而調控血管內皮細胞的再模型化。這些結果推測WMJ-S-001可能可以作為一發展治療癌症轉移的具潛力治療藥物。 Angiogenesis, one of the major routes for tumor invasion and metastasis represents a rational target for therapeutic intervention. Recent development in drug discovery has highlighted the diverse biological and pharmacological properties of hydroxamate derivatives. In this study, we characterized the anti-angiogenic activities of a novel aliphatic hydroxamate, WMJ-S-001, in an effort to develop novel angiogenesis inhibitors. WMJ-S-001 inhibited vascular endothelial growth factor (VEGF)-A-induced proliferation, invasion and endothelial tube formation of human umbilical endothelial cells (HUVECs). WMJ-S-001 suppressed VEGF-A-induced microvessel sprouting from aortic rings, and attenuated angiogenesis in in vivo mouse xenograft models. In addition, WMJ-S-001 inhibited the phosphorylations of VEGFR2, Src, FAK, Akt and ERK in VEGF-A-stimulated HUVECs. WMJ-S-001 caused an increase in SHP-1 phosphatase activity, whereas NSC-87877, a SHP-1 inhibitor, restored WMJ-S-001 suppression of VEGFR2 phosphorylation and cell proliferation. Furthermore, WMJ-S-001 inhibited cell cycle progression and induced cell apoptosis in HUVECs. These results are associated with p53 phosphorylation and acetylation and the modulation of p21 and survivin. Taken together, WMJ-S-001 was shown to modulate vascular endothelial cell remodeling through inhibiting VEGFR2 signaling and induction of apoptosis. These results also support the role of WMJ-S-001 as a potential drug candidate and warrant the clinical development in the treatment of cancer.
Description:	博士指導教授-許準榕共同指導教授-邱文達委員-顏茂雄委員-黃德富委員-蕭哲志
Data Type:	thesis
Appears in Collections:	[Graduate Institute of Medical Sciences] Dissertation/Thesis

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