苯並咪唑衍生物 MPTB誘發人類軟骨瘤細胞凋亡

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 醫學院 > 基礎醫學研究所 > 博碩士論文 > Item 310903500/32572

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题名:	苯並咪唑衍生物 MPTB誘發人類軟骨瘤細胞凋亡 The novel benzimidazole derivative, MPTB, induced cell apoptosis in human chondrosarcoma cells
作者:	林倉裕;Tsang-Yu Lin
贡献者:	醫學院基礎醫學研究所
关键词:	苯並咪唑;軟骨瘤細胞;凋亡;chondrosarcoma;benzimidazole;apoptosis
日期:	2010
上传时间:	2010-09-29 12:13:48 (UTC+8)
摘要:	人類軟骨肉瘤是一種惡性初級的骨頭腫瘤，化學療法和放射性治療對其治療成效不大，新藥之開發時為一件刻不容緩之工作。之前研究表示苯並咪唑衍生物可治療癌症和骨頭方面的病症，以及metabotropic glutamate receptor type 1 (mGlu1) 相關的疾病(如: 抑制神經細胞死亡、帕金森氏症、偏頭痛、大腦栓塞、抗焦慮等…)。本篇論文主要是探討苯並咪唑衍生物 5-methyl-2(pyridine-3-yl)-1-(3,4,5-trimethoxybenzyl) benzimidazole; MPTB對人類軟骨肉瘤細胞的影響，我們發現MPTB對兩株人類軟骨肉瘤細胞株JJ012和 SW1353能誘發細胞凋亡，但對正常軟骨細胞沒有影響，給予細胞 MPTB能誘發粒線體功能缺失和Bak和Bax正向調控，另外一方面MPTB 能觸發內質網壓力及改變細胞質鈣離子的平衡和增加glucose-regulated protein 78 和glucose-regulated protein 94表現，MPTB也增加calpain表現及活性，將glucose-regulated protein 78和calpain siRNA 轉染入細胞能抑制MPTB對JJ012所誘發的細胞凋亡，重要的是動物試驗展現給予MPTB治療 21天後的能抑制腫瘤的生長，在本篇研究中證實MPTB能成為治療人類軟骨腫瘤細胞新的抗癌藥劑。 Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. Therefore, it is important to explore novel and adequate remedies. The benzimidazole derivatives are used for treatment of cancer and bone diseases and treatment of metabotropic glutamate receptor type 1 (mGlu1)-related diseases (epilepsy, inhibition of nerve cell death, Parkinson's disease, migraine headache, cerebral infarction, neurogenic pain, and anxiety disorder). This is the first study of investigate the anticancer effects of the benzimidazole derivative (5-methyl-2(pyridine-3-yl)-1-(3,4,5-trimethoxybenzyl)benzimidazole; MPTB) in human chondrosarcoma cells. Here we found that MPTB induced cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353 but not in primary chondrocytes. Treatment of cells with MPTB induced mitochondrial dysfunction and Bax and Bak up-regulation. On the other hand, MPTB triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol calcium levels, and increased glucose-regulated protein 78 (GRP78) and GRP 94 expression. MPTB also increased calpain expression and activity. Transfection of cells with GRP78 or calpain siRNA reduced MPTB-mediated cell apoptosis in JJ012 cells. Importantly, animal studies have revealed a dramatic 44% reduction in tumor volume after 21 days of treatment. This study demonstrates that MPTB may be a novel anticancer agent for the treatment chondrosarcoma cells.
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