血管新生 (angiogenesis) 是從已存在的血管分化形成新血管網路的過程，對於生理器官發育、組織修復及生殖占有重要調控的角色。在病理中，腫瘤的生長、進展都必須仰賴血管新生，來得到足夠的氧氣和養分供應，以及排除細胞的代謝廢棄物。此外，自體免疫疾病、退化性關節炎及老年性黃斑部病變也與血管過度新生相關，因此，抑制血管新生可應用於血管生成相關的疾病。在本論文中，將探討具有發展潛力的血管新生抑制劑之機轉。
本論文的第一個部分主要在探討來自中草藥廣木香 (Saussurea costus (Falc.) Lipschitz) 的萃取物dehydrocostuslactone (DHC) 對血管新生促進因子 (endothelial growth factors；EGM-2) 引起血管新生的抑制作用與分子機轉。實驗發現，DHC能夠抑制人類臍靜脈內皮細胞的增生及類血管管腔的形成，但是不會影響細胞的移行，在in vivo matrigel plug assay中，DHC能抑制體內的血管新生。DHC能夠透過抑制Akt/GSK-3b、mTOR的磷酸化，明顯減少cyclin D1的蛋白表現，當細胞過度表現持續性活化的 myristoylated (myr)-Akt，DHC抑制細胞增生、管腔形成以及減少cyclin D1都會被逆轉而回復。若是將內皮細胞共同處理LiCl及DHC，則能夠明顯地逆轉DHC抑制細胞生長的作用。總結以上結果，本研究證實Akt/GSK-3b/cyclin D1 以及 mTOR訊息路徑是DHC重要的標靶，因此能夠應用於如癌症及血管新生相關的疾病。
本論文的第二個部分在探討arylsulfonamide 衍生物MPT0G013在體內及體外具有抗血管新生之活性。MPT0G013能明顯抑制內皮細胞增生、移行和類血管管腔形成，經由基因晶片檢測分析，MPT0G013能明顯誘導tissue inhibitors of metalloproteinases 3 (TIMP3) 的表現，將細胞轉染TIMP3 siRNA，能夠逆轉MPT0G013抑制血管新生的作用及回復Akt、ERK蛋白的磷酸化；除此之外，利用in vivo matrigel plug assay和腫瘤的異體移植實驗，證實MPT0G013在體內具有明顯抑制血管生成的作用。因此，我們推論MPT0G013是一個值得進一步研發的抗血管新生藥物。
目前被用來治療癌症的taxanes及vinca生物鹼等微管結合藥物，缺點為抗藥性的產生及必須透過靜脈注射投與，因此迫切需要研發新的藥物。MPT0B271是一個口服生體可用的微管標靶全合成藥物，在體內及體外具有強力的抗癌效果，MPT0B271除了導致微管的去聚合，且能抑制許多癌細胞株生長及降地存活率，包括multidrug-resistant癌細胞株NCI/ADR-RES。利用流式細胞儀分析rhodamine-123 (Rh-123) 的輸出及利用calcein acetoxymethyl ester (calcein AM) assay，發現MPT0B271不是p-glycoprotein (p-gp) 的受質；此外，MPT0B271 也會誘導細胞G2/M期停滯以及細胞凋亡。我們也發現在體內及體外，與單獨給藥相較之下，MPT0B271合併erlotinib (Tarceva) 能明顯抑制人類非小細胞肺癌A549細胞的生長，這些結果證實MPT0B271是一個具有潛力治療各種癌症的新穎的微管結合藥物。
綜合以上所述，本論文主要以抗血管新生及抗癌為研究對象，證實DHC和MPT0G013能顯著抑制體內及體外之血管新生作用，MPT0B271是新穎的抗癌藥物，能夠發展成為治療癌症的先導藥物。

Angiogenesis, which is the process of formation of new blood vessels from pre-existing ones, takes place throughout physiological development, tissue repair, and reproduction. In pathological conditions, angiogenesis is also essential for tumor growth and progression to ensure that more oxygen and nutrients are delivered from the host’s vascular system. Therefore, angiogenesis is a promising target for anticancer treatments. In this thesis, we focused on the discovery of potential novel antiangiogenic agents, and further investigated the mechanism of these agents.
In the first part, we investigated the traditional Chinese medicine component dehydrocostuslactone (DHC) isolated from Saussurea costus (Falc.) Lipschitz, which has been shown to have anti-cancer activity. DHC has an anti-angiogenic effect in the matrigel-plug nude mice model and an inhibitory effect on HUVEC proliferation and capillary-like tube formation in vitro. With respect to the molecular mechanisms underlying the DHC-induced cyclin D1 down-regulation, we demonstrated that DHC significantly inhibited Akt expression, resulting in the suppression of GSK-3b phosphorylation and mTOR expression. Furthermore, the degradation of cyclin D1 and the abrogation of tube formation induced by DHC were significantly reversed by constitutively active myristoylated (myr)-Akt. And the co-treatment with LiCl and DHC significantly reversed the growth inhibition induced by DHC.
Tissue inhibitors of metalloproteinases 3 (TIMP3) were originally characterized as inhibitors of matrix metalloproteinases (MMPs), acting as potent antiangiogenic proteins. In the second part, we demonstrated that the arylsulfonamide derivative MPT0G013 has potent antiangiogenic activities in vitro and in vivo via inducing TIMP3 expression. Treatments with MPT0G013 significantly inhibited endothelial cell functions, such as cell proliferation, migration, and tube formation. Subsequent microarray analysis showed significant induction of TIMP3 gene expression by MPT0G013, and siRNA-mediated blockage of TIMP3 up-regulation abrogated the antiangiogenic activities of MPT0G013 and prevented inhibition of p-AKT and p-ERK proteins. Importantly, MPT0G013 exhibited antiangiogenic activities in in vivo Matrigel plug assays, inhibited tumor growth and up-regulated TIMP3 and p21 proteins in HCT116 mouse xenograft models.
MPT0B271, an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels and reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of p-gp, as determined by flow cytometric analysis of Rh-123 dye efflux and the calcein AM assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by induction of cell apoptosis. We demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the NSCLC A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.
Taken together, the present studies have highlighted the potential application of DHC and MPT0G013 in angiogenesis-related diseases, such as cancer. And the anti-tumor agent MPT0B271 may foster novel therapeutic strategies for various cancer cell lines.

口試委員會審定書……………………………………………………………… I
誌謝……………………………………………………………………………… II
縮寫表…………………………………………………………………………… IV
中文摘要………………………………………………………………………… 1
英文摘要………………………………………………………………………… 3
第一章 緒論
第一節 研究動機與目的………………………………………………5
第二節 文獻回顧………………………………………………………… 6
第二章 實驗材料與方法
第一節 實驗材料………………………………………………………… 28
第二節 實驗方法………………………………………………………… 30
第三章 Dehydrocostuslactone藉由抑制Akt/GSK-3β及mTOR的訊息路徑阻
礙體內及體外的血管新生
中文摘要………………………………………………………………………… 41
英文摘要………………………………………………………………………… 42
第一節 緒言……………………………………………………………… 43
第二節 結果……………………………………………………………… 44
第三節 討論……………………………………………………………… 48
第四章 Arylsulfonamide衍生物MPT0G013藉由增加TIMP3的表現抑制腫
瘤血管新生
中文摘要………………………………………………………………………… 65
英文摘要………………………………………………………………………… 66
第一節 緒言……………………………………………………………… 67
第二節 結果……………………………………………………………… 69
第三節 討論……………………………………………………………… 74
第五章 口服活性微管標靶藥物MPT0B271單獨及與erlotinib合併使用在
治療人類非小細胞肺癌
中文摘要………………………………………………………………………… 94
英文摘要………………………………………………………………………… 95
第一節 緒言……………………………………………………………… 97
第二節 結果……………………………………………………………… 98
第三節 討論……………………………………………………………… 102
第六章 總結與展望…………………………………………………………… 120
參考文獻………………………………………………………………………… 123
著作……………………………………………………………………………… 136

Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, et al. (2006). Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Annals of the New York Academy of Sciences 1091: 151-169.

Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE, et al. (2003). Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene 22(14): 2121-2134.

Akahane T, Akahane M, Shah A, Connor CM, Thorgeirsson UP (2004). TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Experimental cell research 301(2): 158-167.

Algire GH, Chalkley HW, Earle WE, Legallais FY, Park HD, Shelton E, et al. (1950). Vascular reactions of normal and malignant tissues in vivo. III. Vascular reactions'' of mice to fibroblasts treated in vitro with methylcholanthrene. Journal of the National Cancer Institute 11(3): 555-580.

Andrews PD, Knatko E, Moore WJ, Swedlow JR (2003). Mitotic mechanics: the auroras come into view. Current opinion in cell biology 15(6): 672-683.

Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. (2006). Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 12(21): 6494-6501.

BenEzra D (1997). Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Investigative ophthalmology &; visual science 38(12): 2433-2434.

Bond M, Murphy G, Bennett MR, Amour A, Knauper V, Newby AC, et al. (2000). Localization of the death domain of tissue inhibitor of metalloproteinase-3 to the N terminus. Metalloproteinase inhibition is associated with proapoptotic activity. The Journal of biological chemistry 275(52): 41358-41363.

Bond M, Murphy G, Bennett MR, Newby AC, Baker AH (2002). Tissue inhibitor of metalloproteinase-3 induces a Fas-associated death domain-dependent type II apoptotic pathway. The Journal of biological chemistry 277(16): 13787-13795.

Breuninger LM, Paul S, Gaughan K, Miki T, Chan A, Aaronson SA, et al. (1995). Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution. Cancer research 55(22): 5342-5347.

Burgering BM, Coffer PJ (1995). Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376(6541): 599-602.

Canitrot Y, Lautier D (1995). [Use of rhodamine 123 for the detection of multidrug resistance]. Bulletin du cancer 82(9): 687-697.

Carmeliet P (2003). Angiogenesis in health and disease. Nature medicine 9(6): 653-660.

Carmeliet P, Jain RK (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347): 298-307.

Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. (2003). Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17(3): 590-603.

Chen YY, Brown NJ, Jones R, Lewis CE, Mujamammi AH, Muthana M, et al. (2014). A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice. Angiogenesis 17(1): 207-219.

Chung AS, Lee J, Ferrara N (2010). Targeting the tumour vasculature: insights from physiological angiogenesis. Nature reviews. Cancer 10(7): 505-514.

Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, et al. (2007). BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS medicine 4(10): 1669-1679; discussion 1680.

Coulonval K, Kooken H, Roger PP (2011). Coupling of T161 and T14 phosphorylations protects cyclin B-CDK1 from premature activation. Molecular biology of the cell 22(21): 3971-3985.

Davidson G, Niehrs C (2010). Emerging links between CDK cell cycle regulators and Wnt signaling. Trends in cell biology 20(8): 453-460.

Della NG, Campochiaro PA, Zack DJ (1996). Localization of TIMP-3 mRNA expression to the retinal pigment epithelium. Investigative ophthalmology &; visual science 37(9): 1921-1924.

Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes &; development 12(22): 3499-3511.

Diehl JA, Zindy F, Sherr CJ (1997). Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes &; development 11(8): 957-972.

Dumontet C, Jordan MA (2010). Microtubule-binding agents: a dynamic field of cancer therapeutics. Nature reviews. Drug discovery 9(10): 790-803.

Dumontet C, Sikic BI (1999). Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 17(3): 1061-1070.

Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer cell 15(3): 232-239.

El Sayed KA (2005). Natural products as angiogenesis modulators. Mini reviews in medicinal chemistry 5(11): 971-993.

Ellis LM, Hicklin DJ (2008). VEGF-targeted therapy: mechanisms of anti-tumour activity. Nature reviews. Cancer 8(8): 579-591.

Engelman JA (2009). Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature reviews. Cancer 9(8): 550-562.

Fan TJ, Han LH, Cong RS, Liang J (2005). Caspase family proteases and apoptosis. Acta biochimica et biophysica Sinica 37(11): 719-727.

Ferrara N, Kerbel RS (2005). Angiogenesis as a therapeutic target. Nature 438(7070): 967-974.

Fojo T, Menefee M (2007). Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 18 Suppl 5: v3-8.

Folkman J (2007). Angiogenesis: an organizing principle for drug discovery? Nature reviews. Drug discovery 6(4): 273-286.

Folkman J (2002). Role of angiogenesis in tumor growth and metastasis. Seminars in oncology 29(6 Suppl 16): 15-18.

Folkman J (1971). Tumor angiogenesis: therapeutic implications. The New England journal of medicine 285(21): 1182-1186.

Francis H, Solomon B (2010). The current status of targeted therapy for non-small cell lung cancer. Internal medicine journal 40(9): 611-618.

Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, et al. (1995). The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81(5): 727-736.

Franklin SL, Ferry RJ, Jr., Cohen P (2003). Rapid insulin-like growth factor (IGF)-independent effects of IGF binding protein-3 on endothelial cell survival. The Journal of clinical endocrinology and metabolism 88(2): 900-907.

Fu M, Wang C, Li Z, Sakamaki T, Pestell RG (2004). Minireview: Cyclin D1: normal and abnormal functions. Endocrinology 145(12): 5439-5447.

Gavet O, Pines J (2010). Activation of cyclin B1-Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis. The Journal of cell biology 189(2): 247-259.

Gelderblom H, Verweij J, Nooter K, Sparreboom A (2001). Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 37(13): 1590-1598.

Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, et al. (1998). Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3''-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. The Journal of biological chemistry 273(46): 30336-30343.

Gingras AC, Kennedy SG, O''Leary MA, Sonenberg N, Hay N (1998). 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes &; development 12(4): 502-513.

Gottesman MM (2002). Mechanisms of cancer drug resistance. Annual review of medicine 53: 615-627.

Gu P, Xing X, Tanzer M, Rocken C, Weichert W, Ivanauskas A, et al. (2008). Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas. Neoplasia 10(6): 563-572.

Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N (2005). Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. The Journal of biological chemistry 280(37): 32081-32089.

Hamada K, Sasaki T, Koni PA, Natsui M, Kishimoto H, Sasaki J, et al. (2005). The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes &; development 19(17): 2054-2065.

Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B, et al. (2002). Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1. The Journal of biological chemistry 277(19): 16464-16469.

Hawkins T, Mirigian M, Selcuk Yasar M, Ross JL (2010). Mechanics of microtubules. Journal of biomechanics 43(1): 23-30.

Herbert SP, Stainier DY (2011). Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nature reviews. Molecular cell biology 12(9): 551-564.

Herbst RS, Heymach JV, Lippman SM (2008). Lung cancer. The New England journal of medicine 359(13): 1367-1380.

Hoegy SE, Oh HR, Corcoran ML, Stetler-Stevenson WG (2001). Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition. The Journal of biological chemistry 276(5): 3203-3214.

Hopper-Borge E, Chen ZS, Shchaveleva I, Belinsky MG, Kruh GD (2004). Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): resistance to docetaxel. Cancer research 64(14): 4927-4930.

Hsu YL, Wu LY, Kuo PL (2009). Dehydrocostuslactone, a medicinal plant-derived sesquiterpene lactone, induces apoptosis coupled to endoplasmic reticulum stress in liver cancer cells. The Journal of pharmacology and experimental therapeutics 329(2): 808-819.

Huisman MT, Chhatta AA, van Tellingen O, Beijnen JH, Schinkel AH (2005). MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. International journal of cancer. Journal international du cancer 116(5): 824-829.

Hung JY, Hsu YL, Ni WC, Tsai YM, Yang CJ, Kuo PL, et al. (2010). Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells. Lung Cancer 68(3): 355-365.

Ide AG, Baker, N.H. &; Warren, S.L. (1939). Vascularization of the Brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am. J. Roentgenol 42: 891-899.

Ivy SP, Wick JY, Kaufman BM (2009). An overview of small-molecule inhibitors of VEGFR signaling. Nature reviews. Clinical oncology 6(10): 569-579.

Iwatsuki K, Tanaka K, Kaneko T, Kazama R, Okamoto S, Nakayama Y, et al. (2005). Runx1 promotes angiogenesis by downregulation of insulin-like growth factor-binding protein-3. Oncogene 24(7): 1129-1137.

Jiang BH, Liu LZ (2008). AKT signaling in regulating angiogenesis. Current cancer drug targets 8(1): 19-26.

Jiang BH, Zheng JZ, Aoki M, Vogt PK (2000). Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 97(4): 1749-1753.

Kanda S, Hodgkin MN, Woodfield RJ, Wakelam MJ, Thomas G, Claesson-Welsh L (1997). Phosphatidylinositol 3''-kinase-independent p70 S6 kinase activation by fibroblast growth factor receptor-1 is important for proliferation but not differentiation of endothelial cells. The Journal of biological chemistry 272(37): 23347-23353.

Kavallaris M (2010). Microtubules and resistance to tubulin-binding agents. Nature reviews. Cancer 10(3): 194-204.

Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. (2005). EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England journal of medicine 352(8): 786-792.

Koers-Wunrau C, Wehmeyer C, Hillmann A, Pap T, Dankbar B (2013). Cell surface-bound TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival pathways. PloS one 8(7): e70709.

Koolen SL, Beijnen JH, Schellens JH (2010). Intravenous-to-oral switch in anticancer chemotherapy: a focus on docetaxel and paclitaxel. Clinical pharmacology and therapeutics 87(1): 126-129.

Kuo PL, Ni WC, Tsai EM, Hsu YL (2009). Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells. Molecular cancer therapeutics 8(5): 1328-1339.

Lai MJ, Huang HL, Pan SL, Liu YM, Peng CY, Lee HY, et al. (2012). Synthesis and biological evaluation of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indoles as potent histone deacetylase inhibitors with antitumor activity in vivo. Journal of medicinal chemistry 55(8): 3777-3791.

Langton KP, McKie N, Curtis A, Goodship JA, Bond PM, Barker MD, et al. (2000). A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby''s fundus dystrophy. The Journal of biological chemistry 275(35): 27027-27031.

Lens SM, Voest EE, Medema RH (2010). Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nature reviews. Cancer 10(12): 825-841.

Liu H, Tekle C, Chen YW, Kristian A, Zhao Y, Zhou M, et al. (2011). B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Molecular cancer therapeutics 10(6): 960-971.

Lockhart AC, Braun RD, Yu D, Ross JR, Dewhirst MW, Humphrey JS, et al. (2003). Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clinical cancer research : an official journal of the American Association for Cancer Research 9(2): 586-593.

Malumbres M (2011). Physiological relevance of cell cycle kinases. Physiological reviews 91(3): 973-1007.

Miao ZH, Feng JM, Ding J (2012). Newly discovered angiogenesis inhibitors and their mechanisms of action. Acta pharmacologica Sinica 33(9): 1103-1111.

Mollinedo F, Gajate C (2003). Microtubules, microtubule-interfering agents and apoptosis. Apoptosis : an international journal on programmed cell death 8(5): 413-450.

Murphy DA, Makonnen S, Lassoued W, Feldman MD, Carter C, Lee WM (2006). Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). The American journal of pathology 169(5): 1875-1885.

Murray S, Briasoulis E, Linardou H, Bafaloukos D, Papadimitriou C (2012). Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies. Cancer treatment reviews 38(7): 890-903.

Murthy A, Defamie V, Smookler DS, Di Grappa MA, Horiuchi K, Federici M, et al. (2010). Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. The Journal of clinical investigation 120(8): 2731-2744.

Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011). Cyclin D as a therapeutic target in cancer. Nature reviews. Cancer 11(8): 558-572.

Nagase H, Visse R, Murphy G (2006). Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular research 69(3): 562-573.

Nelsen CJ, Rickheim DG, Tucker MM, Hansen LK, Albrecht JH (2003). Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. The Journal of biological chemistry 278(6): 3656-3663.

Nguyen KS, Kobayashi S, Costa DB (2009). Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clinical lung cancer 10(4): 281-289.

Nieto Montesinos R, Beduneau A, Pellequer Y, Lamprecht A (2012). Delivery of P-glycoprotein substrates using chemosensitizers and nanotechnology for selective and efficient therapeutic outcomes. Journal of controlled release : official journal of the Controlled Release Society 161(1): 50-61.

Oh GS, Pae HO, Chung HT, Kwon JW, Lee JH, Kwon TO, et al. (2004). Dehydrocostus lactone enhances tumor necrosis factor-alpha-induced apoptosis of human leukemia HL-60 cells. Immunopharmacology and immunotoxicology 26(2): 163-175.

Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. (2009). Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer cell 15(3): 220-231.

Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. (2005). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS medicine 2(3): e73.

Pavloff N, Staskus PW, Kishnani NS, Hawkes SP (1992). A new inhibitor of metalloproteinases from chicken: ChIMP-3. A third member of the TIMP family. The Journal of biological chemistry 267(24): 17321-17326.

Perez EA (2009). Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Molecular cancer therapeutics 8(8): 2086-2095.

Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C, et al. (2006). Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer cell 10(2): 159-170.

Potente M, Gerhardt H, Carmeliet P (2011). Basic and therapeutic aspects of angiogenesis. Cell 146(6): 873-887.

Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, et al. (2003). A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature medicine 9(4): 407-415.

Qi JH, Ebrahem Q, Yeow K, Edwards DR, Fox PL, Anand-Apte B (2002). Expression of Sorsby''s fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. The Journal of biological chemistry 277(16): 13394-13400.

Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, et al. (1995). Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. The Journal of biological chemistry 270(36): 21176-21180.

Sangodkar J, Katz S, Melville H, Narla G (2010). Lung adenocarcinoma: lessons in translation from bench to bedside. The Mount Sinai journal of medicine, New York 77(6): 597-605.

Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712): 1098-1101.

Schmidt M, Bastians H (2007). Mitotic drug targets and the development of novel anti-mitotic anticancer drugs. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 10(4-5): 162-181.

Schnell CR, Stauffer F, Allegrini PR, O''Reilly T, McSheehy PM, Dartois C, et al. (2008). Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer research 68(16): 6598-6607.

Shapiro AB, Ling V (1998). The mechanism of ATP-dependent multidrug transport by P-glycoprotein. Acta physiologica Scandinavica. Supplementum 643: 227-234.

Shinojima T, Yu Q, Huang SK, Li M, Mizuno R, Liu ET, et al. (2012). Heterogeneous epigenetic regulation of TIMP3 in prostate cancer. Epigenetics : official journal of the DNA Methylation Society 7(11): 1279-1289.

Skeen JE, Bhaskar PT, Chen CC, Chen WS, Peng XD, Nogueira V, et al. (2006). Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer cell 10(4): 269-280.

Stanton RA, Gernert KM, Nettles JH, Aneja R (2011). Drugs that target dynamic microtubules: a new molecular perspective. Medicinal research reviews 31(3): 443-481.

Stewart ZA, Tang LJ, Pietenpol JA (2001). Increased p53 phosphorylation after microtubule disruption is mediated in a microtubule inhibitor- and cell-specific manner. Oncogene 20(1): 113-124.

Szakacs G, Jakab K, Antal F, Sarkadi B (1998). Diagnostics of multidrug resistance in cancer. Pathology oncology research : POR 4(4): 251-257.

Tabata Y, Isashiki Y, Kamimura K, Nakao K, Ohba N (1998). A novel splice site mutation in the tissue inhibitor of the metalloproteinases-3 gene in Sorsby''s fundus dystrophy with unusual clinical features. Human genetics 103(2): 179-182.

Taylor RC, Cullen SP, Martin SJ (2008). Apoptosis: controlled demolition at the cellular level. Nature reviews. Molecular cell biology 9(3): 231-241.

Thomas LW, Lam C, Edwards SW (2010). Mcl-1; the molecular regulation of protein function. FEBS letters 584(14): 2981-2989.

Tsai AC, Pan SL, Liao CH, Guh JH, Wang SW, Sun HL, et al. (2010). Moscatilin, a bibenzyl derivative from the India orchid Dendrobrium loddigesii, suppresses tumor angiogenesis and growth in vitro and in vivo. Cancer letters 292(2): 163-170.

Uribe MC, Grier HJ, Parenti LR (2012). Ovarian structure and oogenesis of the oviparous goodeids Crenichthys baileyi (Gilbert, 1893) and Empetrichthys latos Miller, 1948 (teleostei, Cyprinodontiformes). Journal of morphology 273(4): 371-387.

Ussar S, Voss T (2004). MEK1 and MEK2, different regulators of the G1/S transition. The Journal of biological chemistry 279(42): 43861-43869.

Walker SR, Chaudhury M, Nelson EA, Frank DA (2010). Microtubule-targeted chemotherapeutic agents inhibit signal transducer and activator of transcription 3 (STAT3) signaling. Molecular pharmacology 78(5): 903-908.

Wang CY, Tsai AC, Peng CY, Chang YL, Lee KH, Teng CM, et al. (2012a). Dehydrocostuslactone suppresses angiogenesis in vitro and in vivo through inhibition of Akt/GSK-3beta and mTOR signaling pathways. PloS one 7(2): e31195.

Wang M, Zhao J, Zhang LM, Li H, Yu JP, Ren XB, et al. (2012b). Combined Erlotinib and Cetuximab overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase inhibitor in non-small-cell lung cancer. Journal of cancer research and clinical oncology 138(12): 2069-2077.

Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U (1994). Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby''s fundus dystrophy. Nature genetics 8(4): 352-356.

Yasui M, Yamamoto H, Ngan CY, Damdinsuren B, Sugita Y, Fukunaga H, et al. (2006). Antisense to cyclin D1 inhibits vascular endothelial growth factor-stimulated growth of vascular endothelial cells: implication of tumor vascularization. Clinical cancer research : an official journal of the American Association for Cancer Research 12(15): 4720-4729.

Yuan TL, Choi HS, Matsui A, Benes C, Lifshits E, Luo J, et al. (2008). Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 105(28): 9739-9744.

Zeng Y, Rosborough RC, Li Y, Gupta AR, Bennett J (1998). Temporal and spatial regulation of gene expression mediated by the promoter for the human tissue inhibitor of metalloproteinases-3 (TIMP-3)-encoding gene. Developmental dynamics : an official publication of the American Association of Anatomists 211(3): 228-237.