【作者】 张健；

【导师】 乔士兴；

【作者基本信息】 吉林大学 ， 外科学， 2015， 博士

【摘要】 结肠癌是常见的消化道恶性肿瘤之一，患者术后肿瘤复发、浸润和远处转移等恶性生物学行为，是其主要的死亡原因。有研究证实，CDC25B编码的是一种新的癌基因，过量CDC25B基因表达产物可造成细胞恶性转化和促进肿瘤生长。由于CDC25B与细胞有丝分裂及恶性肿瘤发生关系密切，使其已成为肿瘤生物学及抗肿瘤研究领域的研究热点。有大量研究表明，查尔酮及其衍生物具有良好的抗肿瘤作用，能够从多靶点、多途径抑制多种肿瘤细胞的生物学活性。本课题将结肠癌的生物学特性研究与查尔酮新药研究开发结合在一起，研究查尔酮化合物是否可以通过细胞周期中关键酶的调控，控制结肠癌细胞增殖等生物学行为，进而探究其治疗结肠癌，预防结肠癌复发转移的生物学效应，本研究将对开发新的抗肿瘤药物具有重要现实意义和应用价值。本研究在筛选新合成的系列查尔酮化合物对CDC25B作用基础上，又进行了对CDC25B抑制活性较好的查尔酮化合物K对人结肠癌COLO205细胞系生物学行为干预作用的研究，并对查尔酮化合物K抗结肠癌的作用机制进行了初步探讨，为该药特异性调控结肠癌细胞的生物学特性提供实验基础和理论依据。1.基于CDC25B磷酸酶抑制剂的新型查尔酮衍生物的筛选结论：在19个2，-羟基-4，-异戊烯氧基系列查尔酮衍生物中，有16个化合物对CDC25B磷酸酶有良好的抑制活性。化合物k和r对CDC25B磷酸酶抑制活性最好。化合物k对结肠癌HCT116、肺癌A549、宫颈癌HeLa细胞均有良好的增殖抑制作用。2.查尔酮化合物K对人结肠癌COLO205细胞增殖与凋亡的影响结论：查尔酮化合物K可以在体外抑制COLO205细胞的增殖，并诱导其凋亡。可以作用于Fas/FasL、bcl-2家族，活化Caspase-3，诱导凋亡发生。3.查尔酮化合物K对结肠癌COLO205细胞侵袭和转移的影响结论：查尔酮化合物K能够在体外抑制COLO205细胞的侵袭转移能力，能够下调MMP-2蛋白表达、上调TIMP-2蛋白表达而调控与侵袭转移生物学相关的信号通路的活性，从而发挥抑制侵袭转移的作用。4.查尔酮化合物K对结肠癌COLO205细胞荷瘤鼠的治疗作用结论：查尔酮化合物K治疗的小鼠可以抑制肿瘤的生长和延长生存期，其抑瘤及延长荷瘤鼠生存期效果与伊立替康基本相同。更多还原

【Abstract】 Colon cancer is one of the clinical alimentary canal malignant tumors.Recurrence, infiltration and distant metastasis are the most important causes of death.A number of studies showed that CDC25B code is a new oncogene and excessiveexpression of CDC25B gene can induce cell malignant transformation and tumorgrowth. The research of CDC25B has already become present research focus in thefield of tumor biology and antitumor because CDC25B is closely related to cellmitosis and the occurrence of malignant tumors.Numerous studies demonstrate thatchalcone and its derivatives have a good effect on tumorsThis subject was about biological characteristics research of colon carcinomacombining drug discovery and development of chalcones. Chalcone compoundscontrolling the biological behavior, such as proliferation, of colon cancer through thecell cycle regulation of key enzymes was researched to treatment of colon cancer,prevention of colon cancer recurrence and metastasis. It is of important practicalsignificance and application value in developing new anticancer drugs by thisresearch.Based on the screening of newly-synthesized chalcone compound series andtheir influences on CDC25B, this research furthers to study the biological interventioneffect of chalcone compound K which has a good inhibition activity on CDC25B onhuman colon cancer cell line COLO205. Besides, the preliminary discussion on theanticolon cancer mechanism of chalcone compound K laid an experimental basis andtheoretical foundation for the medicine’s biologically characteristic regulation ofcolon cancer.1.ScreeningofNew-typeChalconeDerivativesofCDC25BPhosphataseInhabitorsConclusion: Among19compounds of2，-hydroxy-4，,-isopentenyl oxylchalcone derivatives,16compounds had good inhibition effect on CDC25Bphosphatase. And compound K and R were the best inhibitors on CDC25B phosphatase. Compound K had good proliferation inhibition effects on carcinoma ofcolon HCT116, lung cancer A549and cervical carcinoma HeLa.2. Influence of Chalcone Compound K on Proliferation and Apoptosis ofCarcinoma of Colon COLO205Conclusion: Chalcone Compound K could inhibit the proliferation of COLO205cells externally and induced their apoptosis. Chalcone Compound K could be alsoapplied to Fas/FasL, bcl-2family, activate Caspase-3and induce apoptosis.3. Influences of Chalcone Compound K on Cell Invasion and Metastasis ofCarcinoma of Colon COLO205Conclusion: Chalcone Compound K could inhibit the cellular invasion ofCOLO205externally, down-regulate the protein expression of MMP-2, andup-regulate the protein expression of TIMP-2so as to control the signaling pathwayactivities related to biological invasion and metastasis and exert its function as theinvasion and metastasis inhibitor.4. Therapeutic Effect on COLO205Cell Tumor-bearing Rats of ChalconeCompound KConclusion: Chalcone Compound K can inhibit the tumor of rats and prolongthe survival lifespan. And the effects of tumor inhinition and lifespan prolongation oftumor-bearing mice are roughly the same to Irinotecan.更多还原