根據(jù)國(guó)際癌癥研究協(xié)會(huì)(IARC)發(fā)表的報(bào)告,肝癌總體上在發(fā)病率方面排名第六,是癌癥相關(guān)死亡的第四大原因。在其治療方面,如果手術(shù)不是一種選擇,可以通過(guò)靶向藥物治療來(lái)控制HCC的蔓延。由于肝臟惡性腫瘤通常在其晚期階段被檢測(cè),因此該疾病是非常致命的,并且在這些階段單獨(dú)或與其他治療模式聯(lián)合化療仍然是在HCC中提供生存益處的最佳可能方式。在過(guò)去的20年中,索拉非尼和雷戈拉非尼是FDA批準(zhǔn)的用于肝癌治療的化學(xué)制劑。雖然這些靶向藥物已經(jīng)適度地改善了中間生存期,但它們未能產(chǎn)生可持續(xù)的生存效益。目前化療藥物的療效有限,缺乏持久反應(yīng),迫切需要開(kāi)發(fā)新的和現(xiàn)代的治療藥物,以提高治療反應(yīng)和最小化對(duì)HCC患者的毒性。救必應(yīng)酸(RA)是一種植物來(lái)源的三萜類(lèi)化合物,文獻(xiàn)報(bào)道具有抗炎和心臟保護(hù)作用。雖然RA及其衍生物可以通過(guò)凋亡誘導(dǎo)多種腫瘤細(xì)胞死亡,但RA對(duì)肝癌的作用及其作用機(jī)制尚不清楚。本文重點(diǎn)研究了RA在體外和體內(nèi)條件下對(duì)肝癌的抗癌作用。MTT,細(xì)胞遷移和侵襲實(shí)驗(yàn)表明,RA可成功抑制Hep G2,SMMC-7721,和內(nèi)皮HUVEC細(xì)胞的細(xì)胞活力,增殖和遷移潛力。通過(guò)軟瓊脂集落形成和克隆形成實(shí)驗(yàn)確定RA對(duì)HCC細(xì)胞...

【文章頁(yè)數(shù)】：108 頁(yè)

【學(xué)位級(jí)別】：博士

【文章目錄】：
Abstract (English)
Abstract (Chinese)
List of abbreviations
Chapter 1: Introduction and review of literature#1 -
    1.1. Cancer
    1.2. Hepatocellular carcinoma (HCC)
    1.3. Hepatocellular carcinoma and angiogenesis
    1.4. Available treatment options for HCC
    1.5. Chemotherapy
        1.5.1. Alkylating agents
        1.5.2. Antimetabolites
        1.5.3. Anti-tumor antibiotics
        1.5.4. Topoisomerase inhibitors
        1.5.5. Vinka alkaloids
        1.5.6. m TOR inhibitors
        1.5.7. Kinase inhibitor drugs
        1.5.8. Neo-adjuvant chemotherapy
        1.5.9. Concomitant Chemo-radiotherapy
        1.5.10. Adjuvant chemotherapy
    1.6. Novel therapeutics
        1.6.1. Targeting Epidermal Growth Factor Receptor in HCC
        1.6.2. Targeting Ras in HCC
        1.6.3. Targeting p53 in HCC
    1.7. Apoptosis
    1.8. Apoptosis: A target for cancer therapy
    1.9. Major cell death and survival pathways in cancer
    1.10. Apoptosis regulators
        1.10.1. Caspase
        1.10.2. Bcl-2 family of proteins
        1.10.3. Cytochrome c
        1.10.4. NFκ B
        1.10.5. VEGF
    1.11. Rotundic acid (RA)
Chapter 2: Materials and reagents
    2.1. Materials
    2.2. Reagents
Chapter 3: Experimental methodologies and protocols
    3.1. Cell culture and maintenance of cell lines
        3.1.1. Revival of cell lines
        3.1.2. Passaging cells
        3.1.3. Cell seeding
        3.1.4. Hemocytometer calculations
        3.1.5. Cryopreservation
    3.2. Drug dilutions and treatments
    3.3. Cell viability assay
    3.4. Colony formation assay
    3.5. Anchorage-independent soft agar colony formation assay
    3.6. Migration assays
    3.7. Invasion assay
    3.8. Gelatin zymography
    3.9. Cell cycle assay
    3.10. DNA damage
    3.11. Annexin V-FITC/PI staining
    3.12. Tube formation assay
    3.13. Immunoblotting
    3.14. VEGF-ELISA
    3.15. Tumor xenograft study
    3.16. CD-31 and TUNEL staining (IHC)
    3.17. Statistical analtsis
Chapter 4: Results
    4.1. Effect of Rotundic acid on the cell viability and proliferation of Hepatocellularcarcinoma cells
    4.2. Effect of Rotundic acid on the migration and invasion of Hepatocellular carcinomacells
    4.3. Effect of Rotundic acid on the MMP secretion in HCC cells
    4.4. Rotundic acid induces S-phase cell cycle arrest in Hep G2 cells
    4.5. Rotundic acid induces apoptosis in Hep G2 cells
    4.6. Effects of RA on endothelial HUVEC cells
    4.7. RA inhibits HCC by modulating AKT/m TOR and MAPK pathways
    4.8. Effects of RA on tumor xenograft mice model of hepatocellular carcinoma
Chapter 5: Discussion and conclusion
References
攻讀博士學(xué)位期間取得的研究成果
List of publications
Acknowledgements
附件



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