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標題: | 草本萃取物結合非侵入式低強度脈衝電場對於胰臟癌細胞與運動神經元細胞受氧化壓力之影響 Effects of herbal treatment combined with non-invasive low intensity pulsed electric field on pancreatic cancer cells and motor neuron cells under oxidative stress |
作者: | Chih-Hsiung Hsieh 謝智雄 |
指導教授: | 趙治宇 |
關鍵字: | 兒茶素,褐藻糖膠,脈衝式電場,胰臟癌,運動神經退化,結合治療,細胞凋亡,神經保護, EGCG,fucoidan,pulsed electric field,pancreatic cancer,motor neurodegeneration,combination treatment,apoptosis,neuroprotection, |
出版年 : | 2019 |
學位: | 博士 |
摘要: | 我們都知道胰臟癌的轉移及惡化速度相當快,令人畏懼;然而傳統療法通常是非常昂貴的,而且可能引起副作用,甚至大多數患者都會歷經痛苦並有復發的風險。另一方面,以漸進性喪失運動神經元為特徵的肌萎縮側索硬化症(ALS),是當前一種毀滅且致命的神經退行性疾病(NDD),但是卻沒有一個有效的治療方法來消除甚至阻止疾病的惡化。因此,開發有效的替代療法來治療這兩種疾病是迫在眉梢的。在本論文中,我們結合了草本分子與非侵入式低強度脈衝電場(low intensity pulsed electric field, LIPEF)作為一種溫和的治療方式,並且我們研究這樣的結合治療在胰臟癌與運動神經退化所產生的協同作用之效益。
首先,我們應用兒茶素(EGCG)和非侵入式LIPEF的組合,以此施加於人類胰臟癌細胞株PANC-1上。實驗結果顯示,EGCG可以降低PANC-1細胞的細胞存活率和遷移能力,並且進一步施加特定強度的LIPEF電刺激後,EGCG誘導的抑制作用顯著地增強。值得注意的是,相同的結合治療對於非惡性的HEK293細胞,幾乎沒有引起細胞活力的抑制作用。我們在此研究中的發現,揭示了結合治療所引起的協同作用,可能劇烈地干擾粒線體,並且增強細胞內在訊號路徑的傳導,所以能夠更有效地誘導細胞凋亡。 接著,我們以運動神經元細胞株NSC-34作為ALS實驗模型,探討褐藻糖膠(fucoidan)與非侵入式LIPEF對過氧化氫(H2O2)引起的神經元損傷所產生的影響。我們發現單獨使用褐藻糖膠處理,可以略微提升H2O2損害下的NSC-34細胞之存活率,並且fucoidan和LIPEF的協同作用則進一步增強了神經保護作用。特別是,我們觀察到LIPEF刺激能明顯抑制H2O2誘發的ROCK蛋白表現,也提升了Akt蛋白的磷酸化。同時,fucoidan調節了Bcl-2家族蛋白的表現,降低了Bax/Bcl-2的比例。除此之外,fucoidan和LIPEF的結合療法還能夠顯著地抑制H2O2引起的神經軸突收縮。 由於草本藥物對於病患而言較為溫和,也有比較高的耐受度,而且非侵入式LIPEF電刺激可以被調整聚焦於特定作用部位,並在草本治療中產生有益的生物效應,因此我們所提出的結合性療法,採用草本分子與非侵入式LIPEF的組合,作用於胰臟癌與運動神經退化性疾病,是一種具有潛力的治療方式,也希望本論文的研究結果能激發更多相關研究。 To date, the rising cost of pancreatic cancer therapies makes it prohibitive. Available therapies commonly cause side effects and lead to high frequency of recurrence. Meanwhile, amyotrophic lateral sclerosis (ALS), featuring the progressive loss of motor neurons, is a devastating and fatal neurodegenerative disease (NDD), without available treatment for ameliorating or even halting the progressive deterioration. Therefore, it is urgent to develop alternative remedy for cost-effective treatment of relevant diseases. In this dissertation, we combined herbal compound with non-invasive low intensity pulsed electric field (LIPEF) as an affordable treatment modality and studied the cooperative effects on treatment of pancreatic cancer and motor neurodegeneration. In the first topic, we applied the combination of epigallocatechin gallate (EGCG) and the non-invasive LIPEF to treat the human pancreatic cell line PANC-1. The results showed that cell viability and migration ability of PANC-1 cells were reduced by EGCG treatment, while EGCG-induced suppressions were stronger by the further exposure of LIPEF with certain intensity (~ 60 V/cm). By contrast, the same combination treatment caused little inhibition of cell viability in non-malignant HEK293 cells. The finding of this study implies that the synergistic reactions in the combination treatment may disturb mitochondria, enhance the intrinsic pathway transduction, and effectively induce apoptosis. In the second topic, the motor neuron-like cell line NSC-34 was employed as an experimental model in probing the effect of fucoidan and the non-invasive LIPEF on the H2O2-induced neuron damage. We found that fucoidan alone could slightly increase the cell viability of the H2O2-treated NSC-34 cells. Further, the protection effect was enhanced by combining the fucoidan treatment with the LIPEF stimulation. Notably, the LIPEF stimulation could attenuate the H2O2-induced expression of ROCK protein and also increase the phosphorylation of Akt. In addition, the administration of fucoidan lessened H2O2-induced increase in the Bax/Bcl-2 ratio. Moreover, this combination treatment could significantly restrain the H2O2-induced neurite retraction. Since herbal agent is mild and tolerable for patients, and the non-invasive LIPEF stimulation could be directed to focus on a specific location and elicit beneficial bioeffects on herbal treatment, we suggest the combination remedy of herbal agent and the non-invasive LIPEF could be a potential alternative treatment for pancreatic cancer and motor neurodegeneration. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78823 |
DOI: | 10.6342/NTU201900423 |
全文授權: | 有償授權 |
顯示於系所單位: | 物理學系 |
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