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研究生(外文):Hui-Wen Hsu
論文名稱(外文):Cytotoxic Effect of S-peptasin and Iso-S-peptasin on the Growth of Human Prostate Cancer Cells
指導教授(外文):Paulus Shyi-Gang Wang
外文關鍵詞:S-petasinProstate cancerApoptosis
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硫蜂斗菜素及異硫蜂斗菜素是由Petasites hybridus的根或葉萃取出來且具有生物活性的成份。Petasites hybridus在古希臘歷史中常用來治療胃腸道的和氣喘。此植物體及其萃取物應用在治療使用上已約有兩千年的歷史,在1994年的研究中指出其粹取物對於人類膀胱癌細胞株(T24)具有抗增殖的效果,且於2000年,本實驗室研究發現其粹取物-硫蜂斗菜素具有抑制大鼠間質細胞分泌睪固酮的效用,然而它對於人類前列腺癌細胞株是否也會造成毒殺效應,目前則尚未有文獻探討。前列腺癌早已成為美國男性最普遍的癌症之一,在台灣,近十年來男性罹患前列腺癌的發生率及死亡率亦逐年增高。在本篇論文研究當中,我選用了三種人類前列腺癌細胞株:LNCaP、DU145以及PC3作為研究對象,探討硫蜂斗菜素及異硫蜂斗菜素對於人類前列腺癌細胞株的抗增殖效應以及其作用機轉,研究過程中所使用的方法分別有:MTT細胞增殖分析法、錐蟲藍染色法、細胞倍增時間計算、光學顯微鏡攝影以及西方墨漬分析法。經由分析細胞增殖及細胞數量變化之後,發現硫蜂斗菜素及異硫蜂斗菜素可以有效的減少細胞數量,若同時以倒立式相位差顯微鏡觀察細胞型態之變化,可發現經過硫蜂斗菜素及異硫蜂斗菜素的刺激,可造成DU145及PC3細胞萎縮、並且有圓起、漂浮的現象,但在LNCaP細胞株中,僅能觀察到細胞有圓起、漂浮的現象,並沒有呈現明顯的萎縮。再以西方墨漬分析法分析與細胞凋亡相關的蛋白質,結果顯示,三種細胞株內的caspase 8、9、3均有被活化的現象,但caspase 7僅在LNCaP及PC3細胞中明顯被活化;此外,三種細胞之細胞質中的cytochrome c蛋白表現量也均因為藥物的刺激而明顯的增加。至於調控cytochrome c釋放的Bax、Bcl-2及p53等蛋白質的表現,在三種細胞中均有不同的表現量變化,在LNCaP細胞中,此三種蛋白的表現量沒有顯著性的差別,但在DU145及PC3細胞中,此三種蛋白質可在硫蜂斗菜素及異硫蜂斗菜素的刺激之下,改變其蛋白含量,調控粒線體內膜中cytochrome c的釋出。除了上述蛋白質的變化,在硫蜂斗菜素及異硫蜂斗菜素的刺激之下,PARP亦有明顯的截切現象,顯示著細胞凋亡的發生。觀看硫蜂斗菜素及異硫蜂斗菜素對於三種人類前列腺癌細胞株之IC50,硫蜂斗菜素對於人類前列腺癌細胞株的抑制生長效果比異硫蜂斗菜素強,並且硫蜂斗菜素及異硫蜂斗菜素對於人類前列腺癌細胞株之細胞倍增時間的抑制效應,遠大於其對於小鼠TM3萊氏細胞株以及人類腎上腺皮質癌細胞株(h295)的影響,亦即表示,相較於其他種細胞株,硫蜂斗菜素及異硫蜂斗菜素可有效的對人類前列腺癌細胞造成細胞凋亡、抑制細胞增殖,且具有相當的特異性。硫蜂斗菜素及異硫蜂斗菜素對於治療前列腺癌的潛力是未來相當值得研究的議題。
S-petasin and iso-S-petasin are bioactive compounds isolated from leaves or roots of Petasites hybridus (Engl. Butterbur; German Pestwure) which has been used therapeutically for more than 2000 years in Greek. It has been reported that the leaf and root extracts of Petasites hybridus relieve gastrointestinal pain, lung-disease such as asthma and cough, as well as spasms of the urogenital-tract, and even suppress the proliferation of human T24 bladder carcinoma cells. In 2000, S-petasin had been found to decrease the testosteron releasing by rat testicular interstitial cells. But few studies about S-petasin and iso-S-petasin on prostate cancer cells have been performed. Prostate cancer has become the most frequently diagnosed, noncutaneous neoplasm and the second leading cancer-related death in the United States. However, during the past 10 years, prostate cancer becomes a more common cancer in Asia. In this study, three prostate cancer cell lines, LNCaP, DU145 and PC3 were used to evaluate the anti-proliferation effects and the underlying mechanisms of S-petasin and iso-S-petasin. MTT assay, trypan blue exclusion, doubling time testing, light microscopic photograph, western blot and a colorimetric assay for caspases were employed in the present study. When MTT assay combined with trypan blue exclusion and doubling time testing, the decrease of cell number caused by S-petasin and iso-S-petasin was conspicuous. Light microscopic photographs of DU145 and PC3 showed that cell became rounded up, shrank and detached from the bottom of the plate. The LNCaP cells didn’t shrink, but showed a rounded up morphology. Protein expressions of apoptosis modulators, such as caspases, PARP, p53, Bcl-2, mitochondrial Bax, cytosolic cytochrome c were analyzed by western blot and colorimetric assays. Results indicated that cytochrome c released from mitochondria in three cell lines. However only p53, mitochondrial Bax and Bcl-2 showed significant changes in DU145 and PC3 cells,. Increase of active form of caspases and decrease of procaspases were also significant in three cell lines. Indeed, PARP was cleaved in the three prostate cancer cell lines when challenged with S-petasin and iso-S-petasin. Moreover, the IC50 of S-petasin on prostate cancer cell lines was lower than that of iso-S-petasin. In addition, the S-petasin or iso-S-petasin induced cell growth inhibition in three prostate cancer cell lines were much higher than that found in mouse TM3 Leydig cells and in human adrenal cortical carcinoma cells ( h295 ). These results suggest that S-petasin and iso-S-petasin selectively suppress the proliferation of androgen-dependent and androgen-independent prostate cancer cell lines by causing apoptosis. The potential of using S-petasin or Iso-S-petasin for treatment of prostate cancer is worthy of further investigation.
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