含肟之類黃酮衍生物, WTC-01, 對於人類鼻咽喉癌細胞之抗癌作用之機轉探討

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題名:	含肟之類黃酮衍生物, WTC-01, 對於人類鼻咽喉癌細胞之抗癌作用之機轉探討 The Mechanism Study of Anticancer Activity of a de novo Oxime-containing Flavonoid Derivative, WTC-01, Against Human Nasopharyngeal Carcinoma Cells.
作者:	李兆勳;Chao-Hsun Lee
貢獻者:	藥學院藥學系碩士班
關鍵詞:	腫瘤;癌症;抗癌;鼻咽喉癌;細胞週期停滯;細胞凋亡;維管束聚合;malignant tumor;cancer;antitumor agent;nasopharyngeal carcinoma;cell cycle arrest;apoptosis;caspase-9;microtubule assembly
日期:	2010
上傳時間:	2010-09-29 14:16:08 (UTC+8)
摘要:	在人類的日常飲食的成分中富含大量的類黃酮，例如：水果、大豆以及蔬菜。許多的研究顯示，類黃酮擁有預防癌症的效用，但是詳細的抗癌機轉卻不是十分的清楚。然而，類黃酮的低溶解度以及尚不甚詳細的抗癌作用機制卻成為了目前臨床使用類黃酮的限制。因此，研究並發展類黃酮及其衍生物來增進治療的效用就顯得格外的重要。 (WTC-01)是實驗室合成的一種含肟之類黃酮衍生物。其對於許多不同來源的癌細胞株都擁有抗細胞增生的能力，包括鼻咽喉癌細胞（NPC-TW01），血癌細胞（MT-2），纖維母細胞瘤（HT-1080），大腸直腸癌細胞（MKN45）以及肺癌細胞（NCI-H661）。其中鼻咽喉癌細胞株（NPC-TW01）對於WTC-01最為敏感，其百分之五十的抑制細胞增生之濃度為0.45 μM。在細胞週期的試驗中，WTC-01在6個小時內就能導致NPC-TW01停滯於 G2 / M時期，並且在藥物處理十二小時後，細胞停滯在G2 / M時期的比例達到最大值。此外，由Annexin-V / PI的鍵結，Hoechst 33258 / PI 雙染，caspase -3被活化以及PARP被切斷激活的實驗結果指出，WTC-01能誘導NPC-TW01行使細胞凋亡。有趣的是，我們的結果顯示出WTC-01能誘導細胞內粒線體膜電位的流失以及caspase -9被活化，而casepase -8卻無任何變化，其意味著WTC-01能誘導NPC-TW01行使粒線體-caspase -9 / -3這條內生路徑行使細胞凋亡。此外，實驗結果也指出WTC-01 能抑制細胞內微導管的聚合，其作用的方式類似於Colchicine。總結來說，種種的結果指出WTC-01能成為抑制微導管聚合之跨世代抗癌新藥，並且有很高的研究價值。 It has been found that flavonoids are rich in human dietary components such as fruits, soy beans, and vegetables. Several studies showed flavonoids could prevent cancer progression effectively, but detail mechanism need to be disclosured. However, low solubility and poor pharmacology profile limit flavonoid’s clinical usage. Therefore, the development of flavonoid derivatives to improve its therapeutic efficacy and pharmacology properties is particularly important. The WTC-01) is one of oxime-containing flavonoid derivatives were synthesized by our laboratory. The anti-proliferative ability was measured by several human cancer cell lines from different origins including nasopharyngeal cancer (NPC-TW01), leukemia (MT-2), fibrosarcoma (HT-1080), gastric adenocarcinoma (MKN45) and lung carcinoma (NCI-H661). Among all the treatment targets, NPC-TW01 is the most sensitive to the WTC-01 treatment with IC50 of 0.45 μM. Cell distribution analysis showed that WTC-01 can cause NPC-TW01 cells arrest in the G2/M phase with 6 hours exposure and the maximum accumulation can be observed by 18 hours. Furthermore, the results of Annexin-V/PI staining, Hoechst 33258/PI double staining, caspase 3 activation and PARP cleavage indicate that WTC-01 induces the apoptotic cell death pathway. Interestingly, our result showed that WTC-01 could cause the loss of mitochondrial transmembrane potential and the activation of caspase-9 without significant activation of the caspase-8, indicating that the WTC01-induced apoptosis in NPC-TW01 depends on the mitochondria and caspase-9/-3 cascades. Further experimental data showed that WTC-01 could inhibit microtubule assembly in vitro and in vivo with similar potency as colchicine. In conclusion, our data demonstrate that WTC-01 has great potential to become the next generation of anti-microtubule drug and worth for further investigation.
顯示於類別:	[藥學系暨碩博士班] 博碩士論文

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