新穎??結構衍生物WTH之抗膠質母細胞瘤作用機轉探討

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題名:	新穎??結構衍生物WTH之抗膠質母細胞瘤作用機轉探討 Investigation of the anti-glioblastoma actions of a novel naphthoquinone derivative, WTH
作者:	陳詠靖 CHEN, YUNG-CHING
貢獻者:	醫學科學研究所碩士班黃?文許銘仁
關鍵詞:	多型性神經膠質母細胞瘤;??結構衍生物;抑制細胞增生;細胞凋亡;cyclin D1;p21;survivin;STAT3;AMPK;p38MAPK glioblastoma (GBM);naphthoquinones;anti-proliferation;apoptosis;cyclin D1;p21;survivin;STAT3;AMPK;p38MAPK
日期:	2023-06-26
上傳時間:	2023-12-15 14:05:11 (UTC+8)
摘要:	多型性神經膠質母細胞瘤 (glioblastoma)是最常見且致死率最高的腦部腫瘤。患者通常接受標準療法：手術切除後接受放療合併使用化療藥物帝盟多 (temozolomide)，許多新穎性治療也應用在再復發的多型性神經膠質母細胞瘤，包括血管新生抑制劑及免疫查核點抑制劑。然而目前臨床上多型性神經膠質母細胞瘤的預後和整體存活率依舊很差，因此迫切需要開發更新穎有效的藥物來對抗多型性神經膠質母細胞瘤。??結構天然物及其衍生物因其廣泛的藥理特性而受到關注，除了抗菌、抗炎、抗血小板等功效外，更被報導具有多樣化抗癌機轉。我們實驗室篩選出一個具有抑制血管新生作用的新穎??結構衍生物WTH，本論文我們進一步探討WTH抗多型性神經膠質母細胞瘤之藥理作用以及其可能機轉。實驗結果顯示WTH能夠抑制神經膠質母細胞瘤細胞增生並誘導細胞凋亡，其機轉可能透過調控細胞週期調控蛋白cyclin D1、p21，以及抗凋亡蛋白survivin的表現。我們也建立神經膠質母細胞瘤原位移植動物模型，實驗結果顯示WTH可抑制神經膠質母細胞瘤在Balb/c裸鼠及C57BL/6小鼠體內的生長。概括來說，WTH 可透過影響神經膠質母細胞瘤細胞內STAT3活性及AMPK-p38MAPK訊息路徑來調控p21、survivin的表現，進而抑制神經膠質母細胞瘤細胞增生並誘導細胞凋亡。 Glioblastoma (GBM) is the most common and deadliest primary brain malignant tumor in adults. Standard treatment of GBM involves surgical resection followed by radiation with concomitant and adjuvant temozolomide chemotherapy. Besides, several novel treatment options for recurrent GBM, include angiogenesis inhibitors and immune checkpoint inhibitors. However, patients with GBM have poor prognoses and overall survival rates. Therefore, the development of novel effective therapeutic strategies is necessary to treat the high incurability of GBM. Natural naphthoquinones and their derivatives have attracted attention due to their broad spectrum of pharmacological properties. In addition to their anti-bacterial, anti-platelet, and anti-inflammatory effects, naphthoquinones have also been reported to have diverse anti-cancer mechanisms. Our laboratory screened out a novel naphthoquinone natural derivative, WTH, which has the effect of inhibiting angiogenesis. In this study, we further explored the possible pharmacological effects of WTH against GBM and its underlying mechanisms. We found that WTH significantly inhibited human GBM cell proliferation and induced cell apoptosis, through modulation of cell cycle regulatory protein, cyclin D1, p21, and antiapoptotic protein, survivin. Then we established GBM orthotopic xenograft mouse model. The in vivo studies demonstrate that WTH suppressed the growth of GBM tumors in both Balb/c nude mice and C57BL/6 mice. Taken together, we demonstrated that WTH modulates the expression of p21 and survivin levels by affecting the STAT3 activity and AMPK-p38MAPK cascade, leading to the anti-proliferative effects and induction of apoptosis in GBM.
描述:	碩士指導教授:黃?文共同指導教授:許銘仁委員:廖彩岑委員:李育誠委員:黃聰龍委員:黃?文委員:許銘仁
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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