臺灣博碩士論文加值系統

白藜蘆醇 (Resveratrol, Resv)已被發現存在於超過70種植物中，例如：虎杖、葡萄、蔓越莓、豆科植物等，這些富含白藜蘆醇的植物常作為健康食品使用。研究發現白藜蘆醇具有廣泛的藥理活性，包括抗癌、抗菌、抗發炎、抗病毒、心血管保護作用、神經保護作用及延緩老化。在台灣，肝癌在男性惡性腫瘤死因中排行第一，於女性中則排行第二。肝癌為死亡率極高，治癒率相當低的癌症，對於目前的化學和放射治療已產生阻抗性。因此本研究目的在於尋找生藥中發展對肝癌有效之藥物。本研究室於先前已證明白藜蘆醇對人類肝癌細胞株Hep G2具有抑制作用，其機轉係透過停止細胞週期於G1期並經由增加p53促進細胞凋亡。本次我們觀察白藜蘆醇對另一種人類肝癌細胞株Huh-7的作用，由XTT結果發現白藜蘆醇對Huh-7亦具有良好毒殺效果，其IC50為22.4μg/mL。由流式細胞儀和DNA fragmentation的觀察可見白藜蘆醇能誘發Huh-7細胞凋亡以及使細胞週期停滯在S期。白藜蘆醇經由p53-independent的方式增加p21/WAF1的活性並減少cyclin A及cyclin E及CDK2的表現，使細胞週期停止於S期。另外白藜蘆醇減少粒腺體中Bcl-2和Bcl-xL的表現，雖然對於Bax的表現沒有影響，但proapoptotic/antiapoptotic protein ratio增加，此結果會造成粒腺體膜電位下降並釋出procaspase 9轉化為活化的caspase 9而誘發細胞凋亡作用。另一方面同時發現白藜蘆醇也會增加caspase 8的活化但不經由Fas/FasL的活化。以白藜蘆醇處理的Huh-7細胞會抑制細胞內ERK1/2和p38的活化。同時利用MEK1/2和p38的抑制劑U0126及SB203580事先處理細胞在加入白藜蘆醇皆明顯增加白藜蘆醇誘導的細胞凋亡。而p38的抑制劑U0126及SB203580會增加白藜蘆醇對caspase 3的活化推測可能是透過活化caspase 8而活化caspase 3，雖然MEK1/2的抑制劑U0126不會對capsase 3的活化造成影響但可能是經由其他路徑調控細胞死亡。由以上結果得知ERK1/2和p38在白藜蘆醇誘導的Huh-7細胞死亡中扮演著重要的角色。除此之外，我們另外發現白藜蘆醇可同時誘導細胞自噬(autophagy)作用，經由增加調控細胞自噬重要分子(Atg proteins)導致細胞死亡。這些結果提供癌症治療的新方向，並證實白藜蘆醇可作為良好治療肝癌的天然藥物。

Resveratrol was rich in more than 70 plants species, including grapes, jackfruit, eucalyptus, rheum, white hellebore. Most of these plants were used as healthy food. Many studies demonstrated that resveratrol has many pharmacological activities, such as anticancer, antibacterial, anti-fungal, anti-aging, anti-inflammatory, antiviral and neuroprotective activity. Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. HCC is a malignancy which has high mortality rate and poor liver cancer survival rate, and most patients are highly resistant to chemotherapy. The goal of this research is to develop effective chemopreventive and chemotherapeutic agents from natural compounds for HCC. The result showed that resveratrol significantly inhibited cell proliferation of Huh-7 and the IC50 of resveratrol was 22.4 μg/mL. We investigated that resveratrol arrest cell cycle at S phase and induced apoptosis. Resveratrol induced the expression of p21/WAF1 in a p53-independent manner and decreased cyclin E, cyclin A and CDK 2 to arrest cell cycle. Otherwise, resveratrol decreased the expression of Bcl-2 and Bcl-xL and did not affect Bax, but the ratio of proapoptotic/ antiapoptotic protein increase. This result means that mitochondria membrane loss and conversion procaspase 9 into active form (caspase 9) to induce apoptosis. We also investigated that resveratrol increased the activity of caspase 8 and did not through Fas/Fas L pathway. Otherwise, we found MEK1/2 and p38 play important roles in resveratrol-mediated Huh-7 cell death. Both the inhibitor of ERK1/2, U0126 and inhibitor of p38, SB203580, significantly increased the cell death. Pretreated SB203580 would increase activity of caspase 3 induced by resveratrol in Huh-7 cell line, but U0126 did not. These results implied a critical role for ERK1/2 and p38 but not p53 and Fas/Fas L in resveratrol-induced cell cycle arrest and apoptotsis. In addition, resveratrol induced not only apoptosis cell death but also autophagy cell death. It increased Atg 5, 7, 9 and 12 which play important roles in autophagy. These investigations provide a new therapeutic strategy for cancer and indicated that resveratrol can be a potential chemopreventive and therapeutic agent.

目錄..............................................I
中文摘要..........................................II
英文摘要..........................................IV
第一章、序論......................................1
第二章、材料與方法................................19
第三章、結果......................................31
第四章、討論......................................37
第五章、參考文獻..................................42
第六章、圖表......................................49
第七章、附圖......................................61

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