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The Mechanisms of Honokiol Inhibits Tumour Growth and Angiogenesis in Gastric Cancer Cells
|關鍵字:||Honokiol;和厚朴酚;Gastric Cancer;胃癌||出版社:||醫學科技研究所||引用:||季宗彬 (2004)，抗癌中藥藥理與應用，黑龍江科學技術出版社。 張永勳 (2008)，中藥學概論，文興出版。 Al-Shammaa,H.A. (2008). Current status and future strategies of cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. Bai,X. (2003). Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. Battle,T.E. (2005). The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Benvenuti,S. (2007). The MET receptor tyrosine kinase in invasion and metastasis. Birchmeier,C. (2003). Met, metastasis, motility and more. Cervantes,A. (2008). The treatment of advanced gastric cancer: current strategies and future perspectives. Chang,B. (1998). Antimicrobial activity of magnolol and honokiol against periodontopathic microorganisms. Chang,Y.W. (2004). 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Background and Aims: Honokiol, a small molecular natural product, has been shown to possess potent anti-neoplastic and anti-angiogenic properties. However, the molecular mechanism underlying the anticancer activity is poorly understood. We examined the in vitro and in vivo effects of PPAR-gamma and c-Met on cell growth, angiogenesis of gastric cancer and the cancer regulated genes-C/EBP beta. Methods: Four gastric cancer cell lines were used. Immunohistochemistry and immunoblotting were used to assess PPAR-gamma and c-Met expression levels in xenograft gastric cancer tumour model and cancer cell lines, respectively. MTT assay, flow cytometry and soft agar assay were used to examine tumour growth. HUVECs tube formation, rat aorta ring assay were employed to assess anti-angiogenic effect. Gelatin zymography, transwell chamber were utilized to investigates invasion and migration. Tumour growth and metastasis were analyzed in mice injected with pure compound Honokiol administered. Moreover, identification of C/EBP beta phosphorylation and translocation were analyzed by immunoprecipitation, nuclear/cytosol protein extraction and immunofluorescence staining assay. Results: PPAR-gamma, c-Met and C/EBP beta overexpression were found in gastric cancer model in vitro and in vivo. Honokiol significantly inhibited tumour growth, migration, invasion and tube formation. In xenograft gastric cancer model,we found Honokiol completely abolished peritoneal metastasis and angiogenesis better than subcutaneous suppressed tumor burden. Activation of calpain II , dephosphorylation and translocation change of C/EBP beta by Honokoil were able to down regulate PPAR-gamma, c-Met and C/EBP beta expression. Conclusions: A novel molecular Honokiol, inhibits tumor growth and angiogenesis, may be a promising drug candidate in anti-angiogenesis and anticancer agent.
背景和目的:和厚朴酚是一個小分子天然化合物，已有研究指出其具有抗腫瘤生長及抗血管新生之功用。然而抗腫瘤作用機轉至今尚未完全釐清，因此我們利用體外及體內試驗來進行分析與腫瘤生長及血管新生相關蛋白 PPAR-gamma和c-Met以及轉錄因子C/EBP beta在胃癌治療之可行性及其作用機轉。實驗方法：以四株胃癌細胞進行實驗。首先利用免疫組織化學染色法及西方墨點法分析裸鼠皮下移植之腫瘤組織及胃癌細胞 PPAR-gamma和c-Met的表現量。細胞生長試驗、流氏細胞分析儀及瓊膠生長測試用來觀察胃癌細胞生長。人類臍帶內皮細胞血管新生試驗、大鼠主動脈環試驗用來分析和厚朴酚的抗血管新生作用。酶譜分析及Transwell chamber侵襲試驗用來研究癌細胞的侵襲和運動能力。裸鼠腫瘤異體移植試驗則用來分析和厚朴酚的抗腫瘤生長及轉移的效力。此外，同時利用免疫沉澱技術、核質蛋白分離及免疫螢光染色觀察轉錄因子C/EBP beta的磷酸化和位移。實驗結果: PPAR-gamma,c-Met和C/EBP beta在胃癌組織和細胞都呈現過量表達。和厚朴酚是透過活化Calpain II、影響C/EBP beta 的磷酸化及位移，降低 PPAR-gamma,c-Met和C/EBP beta在胃癌的表現量，進而抑制腫瘤生長、侵襲及血管新生。此外，在裸鼠體內試驗，和厚朴酚顯著地抑制胃癌細胞腹膜轉移及皮下腫瘤的生長。結論:和厚朴酚有效地抑制胃癌腫瘤生長和血管新
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