碩士 / 國立中山大學 / 生物醫學研究所 / 103 / ABSTRACT
Marine compounds constitute a bountiful resource for drug development against human diseases. A compound derived from marine sponge Hyrtios sp. (Het), has shown excellent potency in suppressing proliferation of hepatoma cells (Huh7 and N1-S1) with the lower half-maximal inhibitory concentrations (IC50). Previous studies indicated that Het inhibited invasion and metastasis of breast cancer cells and it could be used as an apoptotic inducer via inhibiting the NFκB activation. Hepatocellular carcinoma (HCC) is one of the major causes for cancer mortality in Taiwan. The current therapeutic modalities for HCC including the target therapy drug, Sorafenib, remain unsatisfactory in prolonging the survival of HCC patients, underscoring the demand for the development of novel HCC drugs. Therefore, this study was designed to investigate the mechanism of Het on HCC cells and evaluate the therapeutic potential of Het for drug development using animal model.
We found that Het potently suppressed proliferation via Pre-G0 phase block and it also inhibited invasion, colony formation ability of HCC cells. Het attenuated NFκB signaling pathway which plays an important role in HCC cells growth. Moreover, it induced HCC cells and tumor apoptosis and inhibited Ki67 (cell proliferation marker) expression. In tumor growth process, angiogenesis would make the tissue around tumor become blood vessel to nourish itself so that it could invade other tissues. As the result, we evaluate the effect of Het on angiogenesis. We found that Het showed strong potential to suppress proliferation, and migration of endothelial cells (EA. hy926 and HUVEC). Besides, the inhibition of Het in tube formation assay, rat aortic rings assay and on the vascular development in transgenic zebrafish larva Tg(kdrl:mCherryci5-fli1a:negfpy7), indicated that Het could inhibit angiogenesis. We concluded that Het inhibited angiogenesis via attenuating peNOS/eNOS and VEGFR2 expression.
Previous studies indicated that HCC therapy efficiency is associated with cancer stemness and angiogenesis. We further investigated the effect of Het on cancer stemness. However, the results of Het could not inhibit the cancer stemness marker (CD133/ABCG2). Thus, we concluded that Het might toxicity the cancer stem cell to reduce the sphere formation. From our study, Het shows a strong therapeutic potential for HCC therapy because it had the advantage of inhibiting angiogenic activity and its high toxicity to cancer cell.
| Identifer | oai:union.ndltd.org:TW/103NSYS5114010 |
| Date | January 2015 |
| Creators | Tz-Chein Liu, 劉子謙 |
| Contributors | Ming-Hong Tai, 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 | 101 |
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