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研究生:王笠安
研究生(外文):Eric Terry Wang
論文名稱:探討新型核糖核苷酸還原酶抑制劑於大腸直腸癌之機轉
論文名稱(外文):The study for molecular mechanisms of a novel RNR inhibitor in colorectal cancer
指導教授:閰雲
指導教授(外文):Yun Yen
口試委員:董馨蓮林琬琬劉景平
口試委員(外文):Shin-Lian DoongWan-Wan LinJing-Ping Liou
口試日期:2015-07-21
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:臨床藥物基因體學暨蛋白質體學碩士學位學程
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:126
中文關鍵詞:大腸直腸癌鈣池調控鈣離子核糖核苷酸還原酶
外文關鍵詞:Colorectal Cancerstore-operated calciumribonucleotide reductase
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大腸直腸癌為全球發生率位居前三的癌症,在台灣十大死因之中也高居第三。先前研究指出核糖核苷酸還原酶(ribonucleotide reductase)是DNA合成與修復重要的酵素,並在大腸直腸癌之中協助癌細胞的DNA合成與生長,因此核糖核苷酸還原酶抑制劑被視為重要的癌症治療藥物。目前一種新型的核糖核苷酸還原酶抑制劑COH29已進入臨床試驗,其功能為阻擋自由基在核糖核苷酸還原酶子單原RRM1與RRM2之間的傳遞,進而抑制癌細胞DNA之生成。為探討此藥物在大腸直腸癌中的機轉,本實驗研究COH29與大腸直腸癌生長與轉移息息相關的鈣離子之間的訊息傳遞機轉。結果顯示此藥物能夠經由阻擋鈣池調控鈣離子的流入 (store-operated calcium entry),而影響鈣離子調控之粒線體功能與下游路徑,進而抑制大腸直腸癌細胞的發炎反應與侵襲能力。本研究使用微陣列資料與Connectivity Map和LINCS cloud資料庫比對,結果顯示此藥物與許多抗癌藥物具有相同的基因圖譜,更加證明COH29可望能成為有效的抗癌藥物。本研究亦納入418名台灣大腸直腸癌患者,並篩選出2個RRM2B的單一核苷酸基因多型性標地,探討RRM2B基因多型性與大腸直腸癌轉移之相關性。結果顯示當rs2607658帶有T基因型時,大腸直腸癌病人的CEA指數在手術後較容易下降,顯示其成為生物標記的發展性。本研究探討核糖核苷酸還原酶抑制劑COH29在大腸直腸癌細胞之中的抗腫瘤機轉可能是經由抑制鈣池調控鈣離子流入而達成的。經由資料庫分析也發現COH29之基因圖譜和諸多抗腫瘤藥物有相似之處,證實此藥物有開發成為抗腫瘤藥物之潛力,日後將對於大腸直腸癌病患提供更加有效的標靶治療。此外經由基因多型性與大腸直腸癌症的關聯性研究可提供臨床醫師未來能有更精確的診斷與治療。
Colorectal cancer is the leading cancer in incidence and mortality world-wide. Ribonucleotide reductase (RNR) plays indispensable roles in DNA synthesis, growth and metastasis of cancer cells. A promising new drug COH29 has been developed as a RNR inhibitor to inhibit tumor regression in several cancers, such as leukemia and colorectal cancer. COH29 inhibits the enzyme activity by ligand-radical interception and interferes with the RRM1-RRM2 subunits interaction, yet the anti-tumor mechanism has to be further clarified. In this study, we conducted serial translational experiments from clinical genomics to tumor biology. Results showed that COH29 may inhibited colorectal cancer cells progression through the inhibition of store-operated calcium influx and attenuation of mitochondrial calcium influx to influence the functions and signaling of mitochondria. Bioinformatics approaches were performed and results indicated that by querying the COH29 treated HT29 cells gene signature with Connectivity Map and LINCS cloud database, several antineoplastic agents presented similar gene signatures with COH29. In the clinical approach, 418 colorectal cancer patients were recruited. Two single nucleotide polymorphisms (SNPs) of RRM2B were chosen to conduct association study between colorectal cancer progression and RRM2B SNPs. Results indicated patients with T genotype of rs2607658 is associated with decreased of CEA levels after surgery. Our results suggested that RRM2B has association with CEA marker in CRC patients, and the RNR inhibitor COH29 can inhibit colorectal cancer cell metastasis possibly through the attenuation of cellular calcium signaling.  
致謝 I
TABLE OF CONTENTS II
List of Figures and Tables IV
Figures IV
Tables V
中文摘要 1
Abstract 3
Introduction 5
I. Colorectal Cancer 5
II. Store-Operated Calcium Channel (SOC) 14
III. The Development of COH29 20
Materials and Methods 28
I. Cell Lines and Culture 28
II. RNA and Protein Extraction 36
III. Reverse Transcriptase Polymerase Chain Reaction 39
IV. Polymerase Chain Reaction 40
V. Western Blotting 43
VI. Enzyme Linked Immunosorbent Assays (ELISA) 46
VII. Wound Healing Assay 47
VIII. Invasion Assay 48
IX. Extracellular Flux Analyzers 49
X. Intracellular Ion Image Microscopy 51
XI. Flow Cytometry 53
XII. Transmission Electron Microscopy 55
XIII. Microarray Assay 56
XIV. Genotyping Assay 57
Results 59
Conclusions 69
Discussion 71
Figures and Tables 75
References 103
1.Brenner, H., Kloor, M. & Pox, C.P. Colorectal cancer. Lancet 383, 1490-502 (2014).
2.Aklilu, M. & Eng, C. The current landscape of locally advanced rectal cancer. Nat Rev Clin Oncol 8, 649-59 (2011).
3.Hazewinkel, Y. & Dekker, E. Colonoscopy: basic principles and novel techniques. Nat Rev Gastroenterol Hepatol 8, 554-64 (2011).
4.Zauber, A.G., Winawer, S.J., O''Brien, M.J., Lansdorp-Vogelaar, I., van Ballegooijen, M., Hankey, B.F., Shi, W., Bond, J.H., Schapiro, M., Panish, J.F., Stewart, E.T. & Waye, J.D. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 366, 687-96 (2012).
5.Sobin, L.H. & Fleming, I.D. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 80, 1803-4 (1997).
6.Benson, A.B., 3rd, Venook, A.P., Bekaii-Saab, T., Chan, E., Chen, Y.J., Cooper, H.S., Engstrom, P.F., Enzinger, P.C., Fenton, M.J., Fuchs, C.S., Grem, J.L., Hunt, S., Kamel, A., Leong, L.A., Lin, E., Messersmith, W., Mulcahy, M.F., Murphy, J.D., Nurkin, S., Rohren, E., Ryan, D.P., Saltz, L., Sharma, S., Shibata, D., Skibber, J.M., Sofocleous, C.T., Stoffel, E.M., Stotsky-Himelfarb, E., Willett, C.G., Gregory, K.M., Freedman-Cass, D.A. & National Comprehensive Cancer, N. Colon cancer, version 3.2014. J Natl Compr Canc Netw 12, 1028-59 (2014).
7.Van Cutsem, E., Cervantes, A., Nordlinger, B., Arnold, D. & Group, E.G.W. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25 Suppl 3, iii1-9 (2014).
8.Cancer Genome Atlas, N. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330-7 (2012).
9.Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E. & Forman, D. Global cancer statistics. CA Cancer J Clin 61, 69-90 (2011).
10.Boyle, P. & Langman, J.S. ABC of colorectal cancer: Epidemiology. BMJ 321, 805-8 (2000).
11.Garcia-Alvarez, A., Serra-Majem, L., Ribas-Barba, L., Castell, C., Foz, M., Uauy, R., Plasencia, A. & Salleras, L. Obesity and overweight trends in Catalonia, Spain (1992-2003): gender and socio-economic determinants. Public Health Nutr 10, 1368-78 (2007).
12.Center, M.M., Jemal, A. & Ward, E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev 18, 1688-94 (2009).
13.Sung, J.J., Lau, J.Y., Goh, K.L., Leung, W.K. & Asia Pacific Working Group on Colorectal, C. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol 6, 871-6 (2005).
14.Lao, V.V. & Grady, W.M. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 8, 686-700 (2011).
15.Winawer, S.J., Fletcher, R.H., Miller, L., Godlee, F., Stolar, M.H., Mulrow, C.D., Woolf, S.H., Glick, S.N., Ganiats, T.G., Bond, J.H., Rosen, L., Zapka, J.G., Olsen, S.J., Giardiello, F.M., Sisk, J.E., Van Antwerp, R., Brown-Davis, C., Marciniak, D.A. & Mayer, R.J. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112, 594-642 (1997).
16.Potter, J.D. Colorectal cancer: molecules and populations. J Natl Cancer Inst 91, 916-32 (1999).
17.Terzic, J., Grivennikov, S., Karin, E. & Karin, M. Inflammation and colon cancer. Gastroenterology 138, 2101-2114 e5 (2010).
18.Riddell, R.H., Goldman, H., Ransohoff, D.F., Appelman, H.D., Fenoglio, C.M., Haggitt, R.C., Ahren, C., Correa, P., Hamilton, S.R., Morson, B.C. & et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 14, 931-68 (1983).
19.Izcue, A., Coombes, J.L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27, 313-38 (2009).
20.Gabrilovich, D.I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9, 162-74 (2009).
21.Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646-74 (2011).
22.Lengauer, C., Kinzler, K.W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623-7 (1997).
23.Goodin, D.B., Mauk, A.G. & Smith, M. Studies of the radical species in compound ES of cytochrome c peroxidase altered by site-directed mutagenesis. Proc Natl Acad Sci U S A 83, 1295-9 (1986).
24.Wakasugi, K., Sakamoto, M., Nakamura, H. & Igarashi, K. [Serological characteristics of changes in anti-ATLA antibodies using Western blotting method]. Rinsho Ketsueki 29, 787-94 (1988).
25.Markowitz, S.D. & Bertagnolli, M.M. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 361, 2449-60 (2009).
26.Kondo, Y. & Issa, J.P. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev 23, 29-39 (2004).
27.Amado, R.G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D.J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., Patterson, S.D. & Chang, D.D. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26, 1626-34 (2008).
28.Lievre, A., Bachet, J.B., Boige, V., Cayre, A., Le Corre, D., Buc, E., Ychou, M., Bouche, O., Landi, B., Louvet, C., Andre, T., Bibeau, F., Diebold, M.D., Rougier, P., Ducreux, M., Tomasic, G., Emile, J.F., Penault-Llorca, F. & Laurent-Puig, P. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26, 374-9 (2008).
29.Milsom, J.W., Bohm, B., Hammerhofer, K.A., Fazio, V., Steiger, E. & Elson, P. A prospective, randomized trial comparing laparoscopic versus conventional techniques in colorectal cancer surgery: a preliminary report. J Am Coll Surg 187, 46-54; discussion 54-5 (1998).
30.Guillou, P.J., Quirke, P., Thorpe, H., Walker, J., Jayne, D.G., Smith, A.M., Heath, R.M., Brown, J.M. & group, M.C.t. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet 365, 1718-26 (2005).
31.Goldberg, R.M., Fleming, T.R., Tangen, C.M., Moertel, C.G., Macdonald, J.S., Haller, D.G. & Laurie, J.A. Surgery for recurrent colon cancer: strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 129, 27-35 (1998).
32.Van Cutsem, E., Kohne, C.H., Hitre, E., Zaluski, J., Chang Chien, C.R., Makhson, A., D''Haens, G., Pinter, T., Lim, R., Bodoky, G., Roh, J.K., Folprecht, G., Ruff, P., Stroh, C., Tejpar, S., Schlichting, M., Nippgen, J. & Rougier, P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360, 1408-17 (2009).
33.Tol, J., Koopman, M., Cats, A., Rodenburg, C.J., Creemers, G.J., Schrama, J.G., Erdkamp, F.L., Vos, A.H., van Groeningen, C.J., Sinnige, H.A., Richel, D.J., Voest, E.E., Dijkstra, J.R., Vink-Borger, M.E., Antonini, N.F., Mol, L., van Krieken, J.H., Dalesio, O. & Punt, C.J. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360, 563-72 (2009).
34.Karapetis, C.S., Khambata-Ford, S., Jonker, D.J., O''Callaghan, C.J., Tu, D., Tebbutt, N.C., Simes, R.J., Chalchal, H., Shapiro, J.D., Robitaille, S., Price, T.J., Shepherd, L., Au, H.J., Langer, C., Moore, M.J. & Zalcberg, J.R. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359, 1757-65 (2008).
35.Douillard, J.Y., Oliner, K.S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., Rivera, F., Kocakova, I., Ruff, P., Blasinska-Morawiec, M., Smakal, M., Canon, J.L., Rother, M., Williams, R., Rong, A., Wiezorek, J., Sidhu, R. & Patterson, S.D. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369, 1023-34 (2013).
36.Barton, M.K. False elevations of carcinoembryonic antigen levels are common in patients under surveillance for colorectal cancer recurrence. CA Cancer J Clin 64, 365-6 (2014).
37.Clapham, D.E. Calcium signaling. Cell 131, 1047-58 (2007).
38.Berridge, M.J., Bootman, M.D. & Roderick, H.L. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4, 517-29 (2003).
39.Bogeski, I., Kilch, T. & Niemeyer, B.A. ROS and SOCE: recent advances and controversies in the regulation of STIM and Orai. J Physiol 590, 4193-200 (2012).
40.Mikoshiba, K. Role of IP3 receptor signaling in cell functions and diseases. Adv Biol Regul 57, 217-27 (2015).
41.Lewis, R.S. Store-operated calcium channels: new perspectives on mechanism and function. Cold Spring Harb Perspect Biol 3(2011).
42.Parekh, A.B. & Putney, J.W., Jr. Store-operated calcium channels. Physiol Rev 85, 757-810 (2005).
43.Thastrup, O., Cullen, P.J., Drobak, B.K., Hanley, M.R. & Dawson, A.P. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. Proc Natl Acad Sci U S A 87, 2466-70 (1990).
44.Bojarski, L., Pomorski, P., Szybinska, A., Drab, M., Skibinska-Kijek, A., Gruszczynska-Biegala, J. & Kuznicki, J. Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer''s disease. Biochim Biophys Acta 1793, 1050-7 (2009).
45.Feske, S. Immunodeficiency due to defects in store-operated calcium entry. Ann N Y Acad Sci 1238, 74-90 (2011).
46.McCarl, C.A., Picard, C., Khalil, S., Kawasaki, T., Rother, J., Papolos, A., Kutok, J., Hivroz, C., Ledeist, F., Plogmann, K., Ehl, S., Notheis, G., Albert, M.H., Belohradsky, B.H., Kirschner, J., Rao, A., Fischer, A. & Feske, S. ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia. J Allergy Clin Immunol 124, 1311-1318 e7 (2009).
47.Schwarz, E.C., Qu, B. & Hoth, M. Calcium, cancer and killing: the role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells. Biochim Biophys Acta 1833, 1603-11 (2013).
48.Contreras, L., Drago, I., Zampese, E. & Pozzan, T. Mitochondria: the calcium connection. Biochim Biophys Acta 1797, 607-18 (2010).
49.Parekh, A.B. Mitochondrial regulation of store-operated CRAC channels. Cell Calcium 44, 6-13 (2008).
50.Kirichok, Y., Krapivinsky, G. & Clapham, D.E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360-4 (2004).
51.Campanella, M., Pinton, P. & Rizzuto, R. Mitochondrial Ca2+ homeostasis in health and disease. Biol Res 37, 653-60 (2004).
52.Ward, J.P., Snetkov, V.A. & Aaronson, P.I. Calcium, mitochondria and oxygen sensing in the pulmonary circulation. Cell Calcium 36, 209-20 (2004).
53.Rosen, L.B., Ginty, D.D., Weber, M.J. & Greenberg, M.E. Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras. Neuron 12, 1207-21 (1994).
54.Monteith, G.R., Davis, F.M. & Roberts-Thomson, S.J. Calcium channels and pumps in cancer: changes and consequences. J Biol Chem 287, 31666-73 (2012).
55.Roderick, H.L. & Cook, S.J. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer 8, 361-75 (2008).
56.Yang, S., Zhang, J.J. & Huang, X.Y. Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell 15, 124-34 (2009).
57.Chen, Y.F., Chen, Y.T., Chiu, W.T. & Shen, M.R. Remodeling of calcium signaling in tumor progression. J Biomed Sci 20, 23 (2013).
58.Davis, F.M., Azimi, I., Faville, R.A., Peters, A.A., Jalink, K., Putney, J.W., Jr., Goodhill, G.J., Thompson, E.W., Roberts-Thomson, S.J. & Monteith, G.R. Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Oncogene 33, 2307-16 (2014).
59.Nordlund, P. & Reichard, P. Ribonucleotide reductases. Annu Rev Biochem 75, 681-706 (2006).
60.Boukovinas, I., Papadaki, C., Mendez, P., Taron, M., Mavroudis, D., Koutsopoulos, A., Sanchez-Ronco, M., Sanchez, J.J., Trypaki, M., Staphopoulos, E., Georgoulias, V., Rosell, R. & Souglakos, J. Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients. PLoS One 3, e3695 (2008).
61.Jordan, A. & Reichard, P. Ribonucleotide reductases. Annu Rev Biochem 67, 71-98 (1998).
62.Cerqueira, N.M., Fernandes, P.A., Eriksson, L.A. & Ramos, M.J. Ribonucleotide activation by enzyme ribonucleotide reductase: understanding the role of the enzyme. J Comput Chem 25, 2031-7 (2004).
63.Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y. & Nakamura, Y. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404, 42-9 (2000).
64.Shao, J., Zhou, B., Zhu, L., Qiu, W., Yuan, Y.C., Xi, B. & Yen, Y. In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Cancer Res 64, 1-6 (2004).
65.Bourdon, A., Minai, L., Serre, V., Jais, J.P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A. & Rotig, A. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet 39, 776-80 (2007).
66.Pontarin, G., Ferraro, P., Bee, L., Reichard, P. & Bianchi, V. Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells. Proc Natl Acad Sci U S A 109, 13302-7 (2012).
67.Shao, J., Liu, X., Zhu, L. & Yen, Y. Targeting ribonucleotide reductase for cancer therapy. Expert Opin Ther Targets 17, 1423-37 (2013).
68.Simon, G., Sharma, A., Li, X., Hazelton, T., Walsh, F., Williams, C., Chiappori, A., Haura, E., Tanvetyanon, T., Antonia, S., Cantor, A. & Bepler, G. Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 25, 2741-6 (2007).
69.Fan, H., Villegas, C., Huang, A. & Wright, J.A. The mammalian ribonucleotide reductase R2 component cooperates with a variety of oncogenes in mechanisms of cellular transformation. Cancer Res 58, 1650-3 (1998).
70.Zhang, K., Hu, S., Wu, J., Chen, L., Lu, J., Wang, X., Liu, X., Zhou, B. & Yen, Y. Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis. Mol Cancer 8, 11 (2009).
71.Liu, X., Zhou, B., Xue, L., Shih, J., Tye, K., Lin, W., Qi, C., Chu, P., Un, F., Wen, W. & Yen, Y. Metastasis-suppressing potential of ribonucleotide reductase small subunit p53R2 in human cancer cells. Clin Cancer Res 12, 6337-44 (2006).
72.Kolberg, M., Strand, K.R., Graff, P. & Andersson, K.K. Structure, function, and mechanism of ribonucleotide reductases. Biochim Biophys Acta 1699, 1-34 (2004).
73.Liu, X., Zhou, B., Xue, L., Yen, F., Chu, P., Un, F. & Yen, Y. Ribonucleotide reductase subunits M2 and p53R2 are potential biomarkers for metastasis of colon cancer. Clin Colorectal Cancer 6, 374-81 (2007).
74.Shao, J., Zhou, B., Chu, B. & Yen, Y. Ribonucleotide reductase inhibitors and future drug design. Curr Cancer Drug Targets 6, 409-31 (2006).
75.Cerqueira, N.M., Fernandes, P.A. & Ramos, M.J. Understanding ribonucleotide reductase inactivation by gemcitabine. Chemistry 13, 8507-15 (2007).
76.Aye, Y. & Stubbe, J. Clofarabine 5''-di and -triphosphates inhibit human ribonucleotide reductase by altering the quaternary structure of its large subunit. Proc Natl Acad Sci U S A 108, 9815-20 (2011).
77.Koc, A., Wheeler, L.J., Mathews, C.K. & Merrill, G.F. Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools. J Biol Chem 279, 223-30 (2004).
78.Popovic-Bijelic, A., Kowol, C.R., Lind, M.E., Luo, J., Himo, F., Enyedy, E.A., Arion, V.B. & Graslund, A. Ribonucleotide reductase inhibition by metal complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone): a combined experimental and theoretical study. J Inorg Biochem 105, 1422-31 (2011).
79.Aye, Y., Li, M., Long, M.J. & Weiss, R.S. Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies. Oncogene 34, 2011-21 (2015).
80.Zhou, B., Su, L., Hu, S., Hu, W., Yip, M.L., Wu, J., Gaur, S., Smith, D.L., Yuan, Y.C., Synold, T.W., Horne, D. & Yen, Y. A small-molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. Cancer Res 73, 6484-93 (2013).
81.Yen Y, H.D., Yuan Y-C, Zhou B-S, Perkin Harki AL, Su L. Ribonucleotide reductatse inhibitors and methods of use. United States patent US 7956076. (2011).
82.Aye, Y., Brignole, E.J., Long, M.J., Chittuluru, J., Drennan, C.L., Asturias, F.J. & Stubbe, J. Clofarabine targets the large subunit (alpha) of human ribonucleotide reductase in live cells by assembly into persistent hexamers. Chem Biol 19, 799-805 (2012).
83.Chen, M.C., Zhou, B., Zhang, K., Yuan, Y.C., Un, F., Hu, S., Chou, C.M., Chen, C.H., Wu, J., Wang, Y., Liu, X., Smith, D.L., Li, H., Liu, Z., Warden, C.D., Su, L., Malkas, L.H., Chung, Y.M., Hu, M.C. & Yen, Y. The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro. Mol Pharmacol 87, 996-1005 (2015).
84.Prevarskaya, N., Skryma, R. & Shuba, Y. Calcium in tumour metastasis: new roles for known actors. Nat Rev Cancer 11, 609-18 (2011).
85.Schmidt, S., Liu, G., Liu, G., Yang, W., Honisch, S., Pantelakos, S., Stournaras, C., Honig, A. & Lang, F. Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells. Oncotarget 5, 4799-810 (2014).
86.Wang, J.Y., Sun, J., Huang, M.Y., Wang, Y.S., Hou, M.F., Sun, Y., He, H., Krishna, N., Chiu, S.J., Lin, S., Yang, S. & Chang, W.C. STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression. Oncogene (2014).
87.Sun, J., Lu, F., He, H., Shen, J., Messina, J., Mathew, R., Wang, D., Sarnaik, A.A., Chang, W.C., Kim, M., Cheng, H. & Yang, S. STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion. J Cell Biol 207, 535-48 (2014).
88.Sweeney, Z.K., Minatti, A., Button, D.C. & Patrick, S. Small-molecule inhibitors of store-operated calcium entry. ChemMedChem 4, 706-18 (2009).
89.Putney, J.W. Pharmacology of store-operated calcium channels. Mol Interv 10, 209-18 (2010).
90.van der Hoeven, D., Cho, K.J., Ma, X., Chigurupati, S., Parton, R.G. & Hancock, J.F. Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission. Mol Cell Biol 33, 237-51 (2013).
91.Jordheim, L.P., Seve, P., Tredan, O. & Dumontet, C. The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol 12, 693-702 (2011).
92.Liu, X., Zhang, H., Lai, L., Wang, X., Loera, S., Xue, L., He, H., Zhang, K., Hu, S., Huang, Y., Nelson, R.A., Zhou, B., Zhou, L., Chu, P., Zhang, S., Zheng, S. & Yen, Y. Ribonucleotide reductase small subunit M2 serves as a prognostic biomarker and predicts poor survival of colorectal cancers. Clin Sci (Lond) 124, 567-78 (2013).
93.Zhang, H., Liu, X., Warden, C.D., Huang, Y., Loera, S., Xue, L., Zhang, S., Chu, P., Zheng, S. & Yen, Y. Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in estrogen-negative breast cancers. BMC Cancer 14, 664 (2014).
94.Cho, E.C., Kuo, M.L., Liu, X., Yang, L., Hsieh, Y.C., Wang, J., Cheng, Y. & Yen, Y. Tumor suppressor FOXO3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients. Oncotarget 5, 4834-44 (2014).
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