海洋天然物的物種來源有珊瑚、海綿、海鞘、軟體動物、藻及微生物等，這些化合物的生物活性可作為藥物開發來源，被視為治療疾病的重要支柱，但越來越多研究顯示，許多存在於海洋生物中的活性物質，事實上是由共生微生物 (包括細菌、真菌及藻類等)之間化學相互作用所產生，其中以海洋放線菌的二次代謝物被認為在海洋天然物來源貢獻上最為重要。本篇從海洋底泥沉積物篩選出海洋放線菌Streptomyces sp.，利用乙酸乙酯萃取分離出具抗前列腺癌效果的二次代謝物Lu01-M，結果發現，藥物處理對三株前列腺癌細胞之存活率隨著時間或濃度的增加而明顯下降，而以前列腺癌細胞PC3最為敏感，24小時的半抑制濃度 (IC50)為2.45±0.27 μg/mL，同時藥物也會影響癌細胞週期，以及抑制癌細胞增生與遷徙能力。Lu01-M隨著劑量提升會破壞粒線體膜電位，同時誘發活性氧化物與內質網壓力，並抑制p-Akt信號路徑，導致細胞存活率下降。動物實驗結果顯示，Lu01-M可抑制腫瘤生長，且不會對動物本身體重及生化指數造成影響。綜合以上，Lu01-M在抗癌藥物發展上極具有開發之潛力。

There are many sources of marine natural products, including corals, sponges, tunicates, mollusks, algae, and microorganisms. The biological activity of these marine lives can be used as a source of drug development. It is considered as an important pillar for the treatment of diseases, but more and more research shows that many of the active substances present in marine organisms are in fact produced by chemical interactions between symbiotic microorganisms such us bacteria, fungi, algae, etc. The secondary metabolites of marine actinomycetes are considered to be the most important contribution to drug development. This article screened the marine actinomycetes Streptomyces sp., by using ethyl acetate to extract the secondary metabolite, Lu01-M. Lu01-M has anti-prostate cancer effect and the most sensitive cancer cell line was PC3, with IC50 2.45±0.27 μg/mL after 24 hours treatment. Thus, PC3 cells were subjected to further investigation. Lu01-M also affecting cell cycle, inhibited cells proliferation and migration. The use of increasing doses of Lu01-M (0 to 6.25 μg/mL) increased the percentage of disruption of mitochondrial membrane potential, induced the reactive oxygen species and endoplasmic reticulum stress, and inhibited the p-Akt signaling, leading to decrease the cell viability. We further expanded our investigation to evaluate the antitumor effect of Lu01-M in vivo xenograft animal models. Animal experiments showed that Lu01-M could inhibit tumor growth without affecting the body weight of mice and biochemical index. Taken together, these findings suggest that Lu01-M has a great potential in the development of anti-cancer drugs.

第一章、緒論 1
第二章、文獻回顧 5
第三章、研究材料與方法 17
第四章、結果 33
第五章、結論與討論 69

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