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標題: | 心血管及血管新生相關疾病的治療探討: 化合物Pj-8,PPemd26及nstpbp5185之拮抗作用與機制之探討 Therapeutic interventions against cardiovascular and angiogenesis-related diseases: the inhibitory effects and mechanisms of novel compounds, Pj-8, PPemd26 and nstpbp5185 |
作者: | Shiu-Wen Huang 黃綉文 |
指導教授: | 黃德富(Tur-Fu Huang) |
關鍵字: | 血管新生,粥狀動脈硬化,血管內膜增生,發炎反應, angiogenesis,atherosclerosis,restenosis,inflammation, |
出版年 : | 2013 |
學位: | 博士 |
摘要: | 癌症和粥狀動脈動脈硬化相關的心血管疾病是全球發病率和死亡率的主要原因。由於血管內皮生長因子(VEGF)是誘導腫瘤血管生成和轉移的一個關鍵因素,所以VEGF已成為抗血管新生和癌症治療用藥的有效標的。另一方面,近期文獻顯示thromboxane A2 (TXA2) 受體拮抗劑不僅具有抗血小板作用,同時也具有調節血管內皮細胞功能及粥狀動脈硬化疾病進程之發炎反應。近十年來,在治療癌症,免疫疾病,代謝和感染性疾病的小分子抑制劑趨向蓬勃的發展。然而,研究也指出,標靶抑制VEGF-VEGFR訊息或血小板拮抗劑,具有一定的副作用,如出血或胃腸道併發症,因此發展較少併發症之新穎抑制劑,則可提供更多的新穎治療選擇。在論文的第一部分,我們研究關於benzimidazole 及anthraquinone系列的衍生物,PJ-8及PPemd26在人類臍靜脈內皮細胞(HUVEC)的抗血管新生機制。 PJ-8和PPemd26能有效的抑制內皮細胞的增殖、移行、侵入及血管管腔形成的作用。 此外,在小鼠體內實驗中,PJ-8和PPemd26可以有效抑制VEGF誘導或腫瘤誘導的血管生成作用。我們證實PJ-8和PPemd26對血管生成的抑制作用主要是經由抑制VEGFR2訊息傳導而來的。研究結果顯示,PJ-8和PPemd26,是屬於有效,而不會造成毒性的化合物,可以當作前導結構用來研發更有效的針對抑制VEGFR2訊息傳導途徑的小分子化合物,可用於腫瘤之治療及血管新生相關疾病。在論文的第二部分中,我們發現一種新穎的口服有效之抗血小板藥物,TXA2受體拮抗劑,nstpbp5185,並研究其對於抗血管生成,抗發炎,抗氧化及抗粥狀動脈硬化的作用。 Nstpbp5185能抑制VEGF誘導之血管內皮細胞增殖、移行及血管管腔形成,並抑制主動脈環微血管管腔生成。 nstpbp5185也顯著減少在小鼠體內新生血管形成,抑制發炎過程中大鼠初代主動脈平滑肌細胞的增殖和移行而能減少血管內膜異常增生。此外,nstpbp5185能減少發炎刺激下單核球細胞和巨噬細胞吸附到血管內皮細胞的作用而能減少巨噬細胞浸潤作用。在高膽固醇餵食的Apo E缺陷的粥狀動脈硬化的小鼠動物實驗中,證明nstpbp5185可以減少新生內膜的形成及粥狀動脈硬化的病變區域。在Apo E缺陷的老鼠給藥一個月後進行中大腦動脈阻塞中風模式,發現nstpbp5185能減少腦缺血中風的腦部梗塞面積。 此外,在LPS誘導敗血症或肺栓塞之動物實驗中也都能發現nstpbp5185能有效的增加動物的存活率。在動物實驗中也發現,相較於Aspirin,長期服用nstpbp5185並不會造成胃潰瘍及出血的副作用且不會引發肝功能的損害。綜合研究結果顯示,nstpbp5185可能不僅具有抗血小板的作用,它亦具有抗血管新生、抗發炎、抗氧化的作用並能拮抗粥狀動脈硬化之進程,具有保護血管內皮細胞功能和拮抗動脈粥狀硬化的發炎過程。
對於這些小分子化合物詳細的作用機轉及訊息傳導路徑仍須進一步的研究。目前針對癌症、免疫、血栓、代謝及發炎相關疾病的治療之小分子抑制劑,我們正透過循理設計、藥物動力學和毒理研究來增進這些化合物之作用專一性和藥理活性。 Cancers and atherosclerosis-associated cardiovascular diseases are major causes of mortality and morbidity worldwide. As a critical factor in the induction of tumor angiogenesis and metastasis, vascular endothelial growth factor (VEGF) has become an attractive target for anti-angiogenic and cancer therapeutic agents. On the other hand, recent literatures suggest that TP-receptor antagonists not only have antiplatelet effects but also have beneficial effects on endothelial dysfunction and the inflammatory responses involved in atherosclerosis. Recently, the development of small molecule inhibitors in the treatment of cancer, immunological, metabolic and infectious diseases has progressed dramatically. However, several reports indicated that the inhibitors targeting VEGF-VEGFR signaling or anti-platelet agents possess some adverse effects such as bleeding or gastrointestinal complications. Therefore, discovery of new inhibitors with less complications may offer new therapeutic options for the treatment of cancer and atherosclerotic cardiovascular events. In the first part of this study, we have identified two chemicals Pj-8 and PPemd26 from series of benzimidazole and anthraquinone derivatives, respectively, and investigated their anti-angiogenic mechanisms in human umbilical vein endothelial cells (HUVECs). Pj-8 and PPemd26 showed potent inhibitory activity on cell proliferation, migration, invasion, and tube formation of HUVECs. Pj-8 and PPemd26 suppressed VEGF- or tumor-induced angiogenesis in vivo. In addition, we demonstrated that suppression of VEGFR2-mediated signaling contributes to Pj-8 and PPemd26 inhibitory actions on angiogenesis. These results indicate that that Pj-8 and PPemd26 inhibit tumor angiogenesis by targeting the VEGFR2 signaling pathways. They may serve as lead compounds in the development of anti-angiogenic agent in field of cancer and angiogenesis-related diseases. In the second part of this study, we explored and characterized the anti-angiogenic, anti-inflammatory, anti-oxidative and anti-atherosclerotic actions of nstpbp5185, a novel orally selective TP receptor antagonist. Nstpbp5185 inhibited VEGF-induced cell proliferation, migration, invasion, and tube formation of HUVECs and suppressed aorta ring microvessels sprouting. Nstpbp5185 also markedly reduced neovascularization in vivo. Nstpbp5185 also suppressed cell proliferation and migration in rat aorta smooth muscle cells in the inflammation processes, indicating that nstpbp5185 attenuates the neointima formation and restenosis. In addition, nstpbp5185 attenuated monocyte and macrophage adhesion to vascular endothelial cells exposed to inflammatory stimuli, leading to decreased phagocyte infiltration. In the high-cholesterol-diet Apo E-deficient atherosclerosis mouse model, nstpbp5185 was further shown to decrease the neointima formation and aortic atherosclerotic lesion area. Furthermore, nstpbp5185 reduced brain infarction size in an atherosclerosis with MCAO stroke mouse model. Nstpbp5185 also increased survival rate in LPS-induced sepsis model and attenuated pulmonary embolism in pulmonary embolism animal model. Nstpbp5185 has neither gastric ulcerogenic effects, bleeding tendency nor liver damaging effects as compared with aspirin. Collectively, nstpbp5185 possesses pleiotropic pharmacological effects including anti-angiogenic, anti-inflammatory, anti-oxidative and anti-thrombotic activity contributing to its beneficial modulation on endothelial dysfunction, restenosis, atherosclerosis and sepsis. However, the perspective studies regarding their detail mechanism of action and signal transduction pathway involved are still under investigation. Optimization of these compounds in enhancing its potency and specificity is being pursued through rational design, structure-activity relationship, pharmacokinetics and toxicological studies. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15652 |
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