博士 / 國立中山大學 / 海洋生物科技博士學位學程 / 103 / Naturally occurring marine compounds constitute a bountiful drugs resource for human diseases. L is an anti-inflammatory, synthetic intermediate of marine compound E-2 derived from soft coral Cladiella australis. L suppresses the expression of inducible nitric oxide syntheses (iNOS) and cyclooxygenase-II (COX-2) in endotoxin-stimulated macrophage cells, thereby reducing the neointima formation in rat atherosclerosis model. Angiogenesis plays an important role in neointima genesis. Thus, the present study investigated the angiogenic function and mechanism of L. Application of L perturbed the development of intersegmental vessels in transgenic zebrafish. Moreover, L potently suppressed microvessel sprouting in organotypic rat aortic rings. Among cultured endothelial cells, L significantly inhibited MMP-2/MMP-9 expression, cell proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). Mechanistic studies revealed that L significantly reduced the VEGF released by reducing VEGF expression at the mRNA and protein levels. In addition, L reduced surface VEGF receptor 2 (VEGFR2/Flk-1) expressions by repressing the VEGFR2 mRNA level. Finally, an exogenous VEGF supply partially rescued the L-induced angiogenesis blockage in vitro and in vivo.
Hepatocellular carcinoma (HCC) is one of the most common malignancies in Taiwan. Current HCC therapies include surgery, chemotherapy, radiofrequency ablation and target therapy. However, the overall prognosis of the patients with HCC remains poor, underscoring the demand of novel therapeutic agents. In this study, we explored the therapeutic potential and mechanism of L in a pre-clinical HCC model. The therapeutic efficacy of L regimen (10 mg/kg/d) was investigated in rats bearing established Novikoff hepatoma by serial ultrasound (US) and histological studies. In addition, the effect of L on distinct tumor growth processes, including cell proliferation and invasion, as well as colony formation, was studied using N1-S1 and Huh7 cells line. L effectively suppressed the self-renewal and drug-pumping functions by sphere and flow cytometry assay in HCC cells. L also depleted the abundance of CD133/CD44 cancer stem cell markers in HCC cells. A 7-day. L therapy significantly perturbed the progression of rat Novikoff hepatoma. Histological analysis revealed that L therapy result is the same as in vitro.
The process of angiogenesis is crucial for progression and metastasis of the majority of solid tumors including melanomas. In this study, we try to investigate whether angiogenesis is a relevant process in melanoma. We studied this effect and relevant signaling pathways in mouse melanoma cells (B16F10). These findings suggest that L suppressed the metastatic properties, including proliferation, anchorage-independent via colony formation, invasion. L also inhibits the melanoma tumor growth. Above of all, L is an anti-angiogenesis drug which also can inhibit the tumor and tumor stem cells, including melanoma, HCC and other angiogenesis related diseases.
| Identifer | oai:union.ndltd.org:TW/103NSYS5361002 |
| Date | January 2015 |
| Creators | Shih-Wei Lin, 林士為 |
| Contributors | Wen-Shan Li, Ming-Hong Tai, 李文山, 戴明泓 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | en_US |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 124 |
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