Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/81123
標題: Niclosamide 經由Src途徑抑制乳癌細胞生長
Niclosamide inhibits breast cancer progression through Src pathway
作者: 林金瑤
Lin, Chin-Yao
關鍵字: 乳癌;Breast cancer;Src;Src抑制劑;dasatinib;耐克螺;Src;Src inhibitor;dasatinib;niclosamide
出版社: 生命科學院碩士在職專班
引用: 1. Love SM, Barsky SH. Anatomy of the nipple and breast ducts revisited. Cancer. 2004;101(9):1947-57. 2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet. 2013;380(9859):2095-128. 3. 行政院衛生署國民健康局. 中華民國99年癌症登記年度報告: Cancer Registry Annual Report. 2010. 4. Zee KJV, Perez GO, Minnard E, Cohen MA. Preoperative galactography increases the diagnostic yield of major duct excision for nipple discharge. Cancer. 1998;82(10):1874-80. 5. Morris KT, Pommier RF, Morris A, Schmidt WA, Beagle G, Alexander PW, et al. Usefulness of the triple test score for palpable breast masses. Archives of Surgery. 2001;136(9):1008. 6. Lloyd J, Flanagan A. Mammary and extramammary Paget''s disease. Journal of clinical pathology. 2000;53(10):742-9. 7. Edge S, Byrd D, Compton C, Fritz A, Greene F, Trott iA. AJCC cancer staging manual (7th ed). New York, NY:Springer;. 2010. 8. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences. 2001;98(19):10869-74. 9. Prat A, Cheang MCU, Martin M, Parker JS, Carrasco E, Caballero R, et al. Prognostic Significance of Progesterone Receptor–Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer. Journal of Clinical Oncology. 2013;31(2):203-9. 10. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clinical Cancer Research. 2007;13(8):2329-34. 11. Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DS, Nobel AB, et al. Concordance among gene-expression–based predictors for breast cancer. New England Journal of Medicine. 2006;355(6):560-9. 12. Hu Z, Fan C, Oh DS, Marron J, He X, Qaqish BF, et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC genomics. 2006;7(1):96. 13. Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer subtypes and the risk of local and regional relapse. Journal of Clinical Oncology. 2010;28(10):1684-91. 14. Eroles P, Bosch A, Alejandro Perez-Fidalgo J, Lluch A. Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer treatment reviews. 2012;38(6):698-707. 15. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clinical Cancer Research. 2007;13(15):4429-34. 16. Halsted WS. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1889, to January, 1894. Annals of surgery. 1894;20(5):497. 17. Patey D, Dyson W. The prognosis of carcinoma of the breast in relation to the type of operation performed. British journal of cancer. 1948;2(1):7. 18. Fisher B. Systemic chemotherapy as an adjuvant to surgery in the treatment of breast cancer. Cancer. 1969;24(139):125-34. 19. Veronesi U, Saccozzi R, Del Vecchio M, Banfi A, Clemente C, De Lena M, et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. New England Journal of Medicine. 1981;305(1):6-11. 20. Krag D, Weaver D, Alex J, Fairbank J, et al. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surgical oncology. 1993;2(6):335-40. 21. Kootstra JJ, Dijkstra PU, Rietman H, de Vries J, Baas P, Geertzen JH, et al. A longitudinal study of shoulder and arm morbidity in breast cancer survivors 7 years after sentinel lymph node biopsy or axillary lymph node dissection. Breast cancer research and treatment. 2013;139(1):125-34. 22. Schabel F. Concepts for systemic treatment of micrometastases. Cancer. 1975;35(1):15-24. 23. Fisher B. Biological and clinical considerations regarding the use of surgery and chemotherapy in the treatment of primary breast cancer. Cancer. 1977;40(S1):574-87. 24. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. New England Journal of Medicine. 1976;294(8):405-10. 25. Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wigkerham DL, et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. New England Journal of Medicine. 1989;320(8):473-8. 26. Momparler RL, Karon M, Siegel SE, Avila F. Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Research. 1976;36(8):2891-5. 27. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA. Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Molecular pharmacology. 1994;45(4):649-56. 28. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. Journal of Clinical Oncology. 1990;8(9):1483-96. 29. Group EBCTC. Polychemotherapy for early breast cancer: an overview of the randomised trials. The Lancet. 1998;352(9132):930-42. 30. Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, et al. Doxorubicin in combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Annals of Oncology. 2003;14(6):833-42. 31. CTSU RI. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-717. 32. Ling Y-H, Yang Y, Tornos C, Singh B, Perez-Soler R. Paclitaxel-induced apoptosis is associated with expression and activation of c-Mos gene product in human ovarian carcinoma SKOV3 cells. Cancer research. 1998;58(16):3633-40. 33. Torres K, Horwitz SB. Mechanisms of Taxol-induced cell death are concentration dependent. Cancer research. 1998;58(16):3620-6. 34. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Journal of Clinical Oncology. 2003;21(6):976-83. 35. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Journal of clinical oncology. 2005;23(16):3686-96. 36. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla J-P, Weaver C, et al. Adjuvant docetaxel for node-positive breast cancer. New England Journal of Medicine. 2005;352(22):2302-13. 37. Sapunar F, Smith IE. Neoadjuvant chemotherapy for breast cancer. Annals of medicine. 2000;32(1):43-50. 38. Ravdin R, Lewison E, Slack N, Dao T, Gardner B, Fisher B. Results of a clinical trial concerning the worth of prophylactic oophorectomy for breast carcinoma. Surgery, gynecology & obstetrics. 1970;131(6):1055. 39. Jensen EV, Block GE, Smith S, Kyser K, DeSombre ER. Estrogen receptors and breast cancer response to adrenalectomy. National Cancer Institute Monograph. 1971;34(12):55-70. 40. McGuire WL. Estrogen receptors in human breast cancer. Journal of Clinical Investigation. 1973;52(1):73. 41. Chen Y, Schindler M, Simon SM. A mechanism for tamoxifen-mediated inhibition of acidification. Journal of Biological Chemistry. 1999;274(26):18364-73. 42. Miller WR, editor Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Seminars in oncology; 2003;30(14):3-11. 43. Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. The New England journal of medicine. 2005;353(26):2747-57. 44. Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, et al. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. Journal of clinical oncology. 2008;26(12):1948-55. 45. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82. 46. Ravdin PM, Chamness GC. The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: A paradigm for the development of other macromolecular markers-A review. Gene. 1995;159(1):19-27. 47. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer Jr CE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. New England Journal of Medicine. 2005;353(16):1673-84. 48. Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. The lancet oncology. 2011;12(3):236-44. 49. Perez EA, Romond EH, Suman VJ, Jeong J-H, Davidson NE, Geyer CE, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2–positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. Journal of Clinical Oncology. 2011;29(25):3366-73. 50. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. New England Journal of Medicine. 2011;365(14):1273-83. 51. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087-106. 52. Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annual review of cell and developmental biology. 1997;13(1):513-609. 53. Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer and metastasis reviews. 2003;22(4):337-58. 54. Parsons SJ, Parsons JT. Src family kinases, key regulators of signal transduction. Oncogene. 2004;23(48):7906-9. 55. Koch CA, Anderson D, Moran MF, Ellis C, Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991;252(5006):668-74. 56. Sun G, Sharma AK, Budde R. Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation. Oncogene. 1998;17(12):1587. 57. Sun G, Ramdas L, Wang W, Vinci J, McMurray J, Budde RJ. Effect of autophosphorylation on the catalytic and regulatory properties of protein tyrosine kinase Src. Archives of biochemistry and biophysics. 2002;397(1):11-7. 58. Wu L, Bernard-Trifilo JA, Lim Y, Lim S-T, Mitra SK, Uryu S, et al. Distinct FAK-Src activation events promote α5β1 and α4β1 integrin-stimulated neuroblastoma cell motility. Oncogene. 2007;27(10):1439-48. 59. Belsches-Jablonski AP, Biscardi JS, Peavy DR, Tice DA, Romney DA, Parsons SJ. Src family kinases and HER2 interactions in human breast cancer cell growth and survival. Oncogene. 2001;20(12):1465-75. 60. Lesslie D, Summy J, Parikh N, Fan F, Trevino J, Sawyer T, et al. Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases. British journal of cancer. 2006;94(11):1710-7. 61. Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer cell. 2003;4(4):257-62. 62. Penuel E, Martin GS. Transformation by v-Src: Ras-MAPK and PI3K-mTOR mediate parallel pathways. Molecular biology of the cell. 1999;10(6):1693-703. 63. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002;21(13):2000-8. 64. Yu C, Meyer DJ, Campbell GS, Larner AC, CarterSu C, Schwartz J, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995;269(5220):81-3. 65. Sahai E, Olson MF, Marshall C. Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. The EMBO journal. 2001;20(4):755-66. 66. Sieg DJ, Hauck CR, Schlaepfer DD. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. Journal of cell science. 1999;112(16):2677-91. 67. Van Slambrouck S, Grijelmo C, De Wever O, Bruyneel E, Emami S, Gespach C, et al. Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by α1-integrins during colon cancer cell invasion. International journal of oncology. 2007;31(6):1501-8. 68. Webb DJ, Donais K, Whitmore LA, Thomas SM, Turner CE, Parsons JT, et al. FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nature cell biology. 2004;6(2):154-61. 69. Dehm SM, Bonham K. SRC gene expression in human cancer: the role of transcriptional activation. Biochemistry and cell biology. 2004;82(2):263-74. 70. Ottenhoff-Kalff A, Rijksen G, Van Beurden E, Hennipman A, Michels A, Staal G. Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product. Cancer research. 1992;52(17):4773-8. 71. Verbeek BS, Vroom TM, Adriaansen‐Slot SS, Ottenhoff‐Kalff AE, Geertzema JG, Hennipman A, et al. c‐Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. The Journal of pathology. 1996;180(4):383-8. 72. Biscardi JS, Belsches AP, Parsons SJ. Characterization of human epidermal growth factor receptor and c‐Src interactions in human breast tumor cells. Molecular carcinogenesis. 1998;21(4):261-72. 73. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707-12. 74. Zhang L, Teng Y, Zhang Y, Liu J, Xu L, Qu J, et al. c‐Src expression is predictive of poor prognosis in breast cancer patients with bone metastasis, but not in patients with visceral metastasis. Apmis. 2012;120(7):549-57. 75. Evan YY, Wilding G, Posadas E, Gross M, Culine S, Massard C, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clinical Cancer Research. 2009;15(23):7421-8. 76. Lara Jr PN, Longmate J, Evans CP, Quinn DI, Twardowski P, Chatta G, et al. A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study. Anti-cancer drugs. 2009;20(3):179. 77. Vultur A, Buettner R, Kowolik C, Liang W, Smith D, Boschelli F, et al. SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Molecular cancer therapeutics. 2008;7(5):1185-94. 78. Mayer E, Baurain J, Sparano J, Strauss L, Campone M, Fumoleau P, et al. Dasatinib in advanced HER2/neu amplified and ER/PR-positive breast cancer: Phase II study CA180088. J Clin Oncol. 2009;27(15S):1011. 79. Somlo G, Atzori F, Strauss L, Rybicki A, Wu X, Gradishar W, et al. Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): phase I study CA180004. J Clin Oncol. 2009;27(15S):1012. 80. Haura EB, Tanvetyanon T, Chiappori A, Williams C, Simon G, Antonia S, et al. Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non–small-cell lung cancer. Journal of Clinical Oncology. 2010;28(8):1387-94. 81. Miller AA, Pang H, Hodgson L, Ramnath N, Otterson GA, Kelley MJ, et al. A Phase II Study of Dasatinib in Patients with Chemo-sensitive Relapsed Small Cell Lung Cancer (CALGB 30602). Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2010;5(3):380. 82. Finn RS, Bengala C, Ibrahim N, Roche H, Sparano J, Strauss LC, et al. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clinical Cancer Research. 2011;17(21):6905-13. 83. Fornier M, Morris P, Abbruzzi A, D''Andrea G, Gilewski T, Bromberg J, et al. A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer. Annals of oncology. 2011;22(12):2575-81. 84. Mayer EL, Baurain J-F, Sparano J, Strauss L, Campone M, Fumoleau P, et al. A Phase 2 Trial of Dasatinib in Patients with Advanced HER2-Positive and/or Hormone Receptor–Positive Breast Cancer. Clinical cancer research. 2011;17(21):6897-904. 85. Somlo G, Atzori F, Strauss LC, Geese WJ, Specht JM, Gradishar WJ, et al. Dasatinib plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy in Phase I Study CA180004. Clinical Cancer Research. 2013;19(7):1884-93. 86. Mayer EL, Krop IE. Advances in targeting SRC in the treatment of breast cancer and other solid malignancies. Clinical Cancer Research. 2010;16(14):3526-32. 87. Pan J, Ding K, Wang C. Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells. Chinese journal of cancer. 2012;31(4):178. 88. Jin Y, Lu Z, Ding K, Li J, Du X, Chen C, et al. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-κB pathway and generation of reactive oxygen species. Cancer research. 2010;70(6):2516-27. 89. Osada T, Chen M, Yang XY, Spasojevic I, Vandeusen JB, Hsu D, et al. Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer research. 2011;71(12):4172-82. 90. Sack U, Walther W, Scudiero D, Selby M, Kobelt D, Lemm M, et al. Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. Journal of the National Cancer Institute. 2011;103(13):1018-36. 91. Rocca A, Paradiso A, Sismondi P. Growth Inhibition of Ovarian Tumor–Initiating Cells by Niclosamide. Molecular Cancer Therapeutics. 2012;11(8):1703-12. 92. Chen M, Wang J, Lu J, Bond MC, Ren X-R, Lyerly HK, et al. The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry. 2009;48(43):10267-74. 93. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Reviews Drug Discovery. 2009;8(7):579-91. 94. Wang AM, Ku HH, Liang YC, Chen YC, Hwu YM, Yeh TS. The autonomous notch signal pathway is activated by baicalin and baicalein but is suppressed by niclosamide in K562 cells. Journal of cellular biochemistry. 2009;106(4):682-92. 95. Balgi AD, Fonseca BD, Donohue E, Tsang TC, Lajoie P, Proud CG, et al. Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One. 2009;4(9):e7124. 96. Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, et al. Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Medicinal Chemistry Letters. 2010;1(9):454-9. 97. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. Journal of Clinical Oncology. 2008;26(8):1275-81. 98. Colleoni M, Cole BF, Viale G, Regan MM, Price KN, Maiorano E, et al. Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. Journal of clinical oncology. 2010;28(18):2966-73. 99. Cheang M, Chia S, Tu D, Jiang S, Shepherd L, Pritchard K, et al. Anthracyclines in basal breast cancer: the NCIC-CTG trial MA5 comparing adjuvant CMF to CEF. Journal of clinical oncology. 2009;27(15s):519. 100. A Rocca, A Paiadiso, P Sismondi. Benefit from CMF with or without anthracyclines in relation to biologic profiles in early breast cancer. Journal of clinical oncology. 2011;29:87. 101. Martin M, Segui MA, Anton A, Ruiz A, Ramos M, Adrover E, et al. Adjuvant docetaxel for high-risk, node-negative breast cancer. New England Journal of Medicine. 2010;363(23):2200-10. 102. Hugh J, Hanson J, Cheang MCU, Nielsen TO, Perou CM, Dumontet C, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. Journal of Clinical Oncology. 2009;27(8):1168-76. 103. Nautiyal J, Majumder P, Patel BB, Lee FY, Majumdar AP. Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling. Cancer letters. 2009;283(2):143-51. 104. Lipfert L, Haimovich B, Schaller MD, Cobb BS, Parsons JT, Brugge JS. Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. The Journal of Cell Biology. 1992;119(4):905-12. 105. Finn RS, Dering J, Ginther C, Wilson CA, Glaspy P, Tchekmedyian N, et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast cancer research and treatment. 2007;105(3):319-26. 106. Summy JM, Gallick GE. Treatment for advanced tumors: SRC reclaims center stage. Clinical Cancer Research. 2006;12(5):1398-401.
摘要: 
三陰性乳癌(triple negative breast cancer)一般認為是乳癌中病程進展較快的亞型,有較高比例造成局部復發、遠端器官的轉移及死亡。這類患者對化學治療的反應比較好,但是主要的全身性治療也只有化學治療。找出新的藥物若能增加化學治療的效果,以減少三陰性乳癌患者的復發或轉移是必要的。Src是一種酪氨酸激酶,屬於Src酪氨酸激酶家族(Src family kinases; SFKs)的一員,能調節多個與酪氨酸激酶相關的細胞膜間接受體誘使細胞內標靶蛋白的活化,包括PI3-kinase, focal adhesion kinase (FAK)及signal transducers and activators of transcription 3 (Stat3)。在多項癌症研究中發現,當Src路徑被活化可能促進癌細胞增生、存活、分化、移動及侵犯等。乳癌的研究發現表皮生長因子接受體(Epidermal Growth Factor Receptor; EGFR)會活化及增加Src的活性,在乳癌合併骨頭轉移的患者,Src的表現也代表較差的預後。因此,抑制Src的藥物可能對於乳癌的治療有所幫助。單獨使用Src抑制劑Dasatinib或Bosutinib在乳癌的治療效果並不理想。本實驗室發現耐克螺(niclosamide)可以抑制Src活性及肺癌細胞存活能力,並誘導細胞凋亡,推測耐克螺可能是具有臨床治療潛力的Src抑制劑。耐克螺是一種口服的驅蟲藥,主要使用於絛蟲感染的患者,研究發現,耐克螺可以抑制癌細胞的增生、遷移及侵襲。我們發現在耐克螺處理72 小時後,細胞的存活率隨著藥物濃度顯著降低。此外,表皮生長因子接受體、磷酸化的FAK、FAK、磷酸化的Stat-3和Stat-3的活性皆被抑制。耐克螺可抑制細胞遷移,侵襲和聚落形成。我們的研究顯示,耐克螺可能經由Src的途徑抑制乳癌的進展。在未來,化學治療合併耐克螺治療可能是乳癌治療的選項,尤其是在三陰性乳腺癌患者。

Triple negative breast cancer is generally considered the rapid progression of breast cancer subtype, resulting in a higher propotion of local recurrence, distant metastasis and death. These patients are sensitive to chemotherapy, but the main systemic therapy of them is only the chemotherapy. It is necessary to find new drugs to increase the effects of chemotherapy to reduce recurrence or metastasis of triple negative breast cancer. Src is a tyrosine kinase, and belongs to Src family kinases (SFKs). SFKs regulate signaling from multiple transmembrane receptor-associated tyrosine kinases and lead to activation of intracellular target proteins including PI3-kinase, focal adhesion kinase (FAK) and signal transducers and activators of transcription 3 (Stat3). In a number of various cancer studies, they found that the activation of Src pathway promotes cancer cell proliferation, survival, differentiation, migration and invasion. EGFR activates Src and also increases the activity of Src in breast cancer research. In breast cancer patient with bone metastasis, expression of the Src also represents a poor prognosis. Therefore, Src inhibitor maybe helpful for the treatment of breast cancer. Src inhibitor, Dasatinib or Bosutinib, use alone in breast cancer treatment is not ideal. Our lab found that niclosamide can inhibit activity of Src and lung cancer cell viability and induction of apoptosis, suggesting that niclosamide may have clinical potential and serve as a Src inhibitor. Niclosamide is an oral anthelmintic, mainly used in tapeworm infected patients, our study found that niclosamide can inhibit cancer cell proliferation, migration and invasion. We found that treated cancer cells with Niclosamide for 72 hours, the cell viability reduced significantly and in a concentration-dependent manner. In addition, the activity of EGFR, phospho-FAK, FAK, phospho-Stat-3 and Stat-3 were to be suppressed. The treatment with Niclosamide significantly increased the apoptosis. Furthermore, the effects of niclosamide may inhibit cell migration, invasion and colony formation. Our research shows that niclosamide might inhibit breast cancer progression through Src suppression pathway. In the future, combined chemotherapy with niclosamide may be considered beneficial for breast cancer treatment, especially in triple negative breast cancer patients.
URI: http://hdl.handle.net/11455/81123
其他識別: U0005-2508201318194900
Appears in Collections:生命科學院

Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.