therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci 1091: 151–169. 19. Burris H, Moore M, Andersen J, Green M, Rothenberg M, et al. (1997) Improvements in survival and clinical benefit with gemcitabine as first- line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology 15: 2403–2413. 20. Changelian PS, Moshinsky D, Kuhn CF, Flanagan ME, Munchhof MJ, et al. (2008) The specificity of JAK3 kinase inhibitors. Blood 111: 2155–2157. 21. Tomillero A, Moral MA (2009) Gateways to clinical trials. Methods Find Exp Clin Pharmacol 31: 661–700. 22. Shankar S, Ganapathy S, Hingorani SR, Srivastava RK (2008) EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. Front Biosci 13: 440–452. 23. Shankar S, Ganapathy S, Srivastava RK (2007) Green tea polyphenols: biology and therapeutic implications in cancer. Front Biosci 12: 4881–4899. 24. Shankar S, Suthakar G, Srivastava RK (2007) Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer. Front Biosci 12: 5039–5051. 25. Liang Y-C, Lin-shiau S-Y, Chen C-F, Lin J-K (1997) Suppression of extracellular signals and cell proliferation through EGF receptor binding by (2)-epigallocatechin gallate in human A431 epidermoid carcinoma cells. Journal of Cellular Biochemistry 67: 55–65. 26. Ahmad N, Feyes DK, Agarwal R, Mukhtar H, Nieminen A-L (1997) Green Tea Constituent Epigallocatechin-3-Gallate and Induction of Apoptosis and Cell Cycle Arrest in Human Carcinoma Cells. Journal of the National Cancer Institute 89: 1881–1886. 27. Cao Y, Cao R (1999) Angiogenesis inhibited by drinking tea. Nature 398: 381–381. 28. Gupta S, Hastak K, Afaq F, Ahmad N, Mukhtar H (2004) Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappaB and induction of apoptosis. Oncogene 23: 2507–2522. 29. Shimizu M, Deguchi A, Lim JTE, Moriwaki H, Kopelovich L, et al. (2005) (2)- Epigallocatechin Gallate and Polyphenon E Inhibit Growth and Activation of the Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor-2 Signaling Pathways in Human Colon Cancer Cells. Clinical Cancer Research 11: 2735–2746. 30. Adhami VM, Siddiqui IA, Ahmad N, Gupta S, Mukhtar H (2004) Oral Consumption of Green Tea Polyphenols Inhibits Insulin-Like Growth Factor-I– Induced Signaling in an Autochthonous Mouse Model of Prostate Cancer. Cancer Research 64: 8715–8722. 31. Dong Z, Ma W-y, Huang C, Yang CS (1997) Inhibition of Tumor Promoter- induced Activator Protein 1 Activation and Cell Transformation by Tea Polyphenols, (2)-Epigallocatechin Gallate, and Theaflavins. Cancer Research 57: 4414–4419. 32. Nam S, Smith DM, Dou QP (2001) Ester Bond-containing Tea Polyphenols Potently Inhibit Proteasome Activity in Vitro and in Vivo. Journal of Biological Chemistry 276: 13322–13330. 33. Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, et al. (2008) Stat3 Promotes Metastatic Progression of Prostate Cancer. Am J Pathol 172: 1717–1728. 34. Porter AG, Ja¨nicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell death and differentiation 6: 99–104. 35. Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, et al. (2001) Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 7: 108–113. 36. Levy DE, Darnell JE (2002) STATs: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3: 651–662. 37. Kudlacz E, Perry B, Sawyer P, Conklyn M, McCurdy S, et al. (2004) The Novel JAK-3 Inhibitor CP-690550 Is a Potent Immunosuppressive Agent in Various Murine Models. American Journal of Transplantation 4: 51–57. 38. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer Statistics, 2010. CA: A Cancer Journal for Clinicians 60: 277–300. 39. Ghaneh P, Costello E, Neoptolemos JP (2007) Biology and management of pancreatic cancer. Gut 56: 1134–1152. 40. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, et al. (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53: 549–554. 41. Schlieman MG, Fahy BN, Ramsamooj R, Beckett L, Bold RJ (2003) Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J Cancer 89: 2110–2115. 42. Zapatka M, Zboralski D, Radacz Y, Bockmann M, Arnold C, et al. (2006) Basement membrane component laminin-5 is a target of the tumor suppressor Smad4. Oncogene 26: 1417–1427. 43. Levy L, Hill CS (2005) Smad4 Dependency Defines Two Classes of Transforming Growth Factor {beta} (TGF-{beta}) Target Genes and Distinguishes TGF-{beta}-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses. Mol Cell Biol 25: 8108–8125. 44. Kayed H, Kleeff J, Osman T, Keleg S, Bu¨ chler MW, et al. (2006) Hedgehog Signaling in the Normal and Diseased Pancreas. Pancreas 32: 119–129. 110.1097/1001.mpa.0000202937.0000255460.0000202930c. 45. Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchier M, et al. (1992) Overexpression of the epidermal growth factor receptor in human pancreatic STAT3 Signaling in Pancreatic Cancer cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. The Journal of Clinical Investigation 90: 1352–1360. 46. Sporn MB (1976) Approaches to Prevention of Epithelial Cancer during the Preneoplastic Period. Cancer Research 36: 2699–2702. 47. Dreosti IE, Wargovich MJ, Yang CS (1997) Inhibition of carcinogenesis by tea: The evidence from experimental studies. Critical Reviews in Food Science and Nutrition 37: 761–770. 48. Fujiki H, Suganuma M, Imai K, Nakachi K (2002) Green tea: cancer preventive beverage and/or drug. Cancer Letters 188: 9–13. 49. Nakachi K, Matsuyama S, Miyake S, Suganuma M, Imai K (2000) Preventive effects of drinking green tea on cancer and cardiovascular disease: Epidemio- logical evidence for multiple targeting prevention. BioFactors 13: 49–54. 50. Yu G-p, Hsieh C-c, Wang L-y, Yu S-z, Li X-l, et al. (1995) Green-tea consumption and risk of stomach cancer: a population-based case-control study in Shanghai, China. Cancer Causes and Control 6: 532–538. 51. Stoner GD, Mukhtar H (1995) Polyphenols as cancer chemopreventive agents. Journal of Cellular Biochemistry 59: 169–180. 52. Ahn H-Y, Hadizadeh KR, Seul C, Yun Y-P, Vetter H, et al. (1999) Epigallocathechin-3 Gallate Selectively Inhibits the PDGF-BB-induced Intra- cellular Signaling Transduction Pathway in Vascular Smooth Muscle Cells and Inhibits Transformation of sis-transfected NIH 3T3 Fibroblasts and Human Glioblastoma Cells (A172). Mol Biol Cell 10: 1093–1104. 53. Ji B-T, Chow W-H, Hsing AW, McLaughlin JK, Dai Q, et al. (1997) Green tea consumption and the risk of pancreatic and colorectal cancers. International Journal of Cancer 70: 255–258. 54. Dauer DJ, Ferraro B, Song L, Yu B, Mora L, et al. (2005) Stat3 regulates genes common to both wound healing and cancer. Oncogene 24: 3397–3408. 55. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, et al. (2008) NF-[kgr]B links innate immunity to the hypoxic response through transcriptional regulation of HIF-1[agr]. Nature 453: 807–811. 56. Karin M, Lin A (2002) NF-[kappa]B at the crossroads of life and death. Nat Immunol 3: 221–227. 57. Naugler WE, Karin M (2008) NF-[kappa]B and cancer–identifying targets and mechanisms. Current Opinion in Genetics & Development 18: 19–26. 58. Grivennikov SI, Karin M (2010) Dangerous liaisons: STAT3 and NF-kB collaboration and crosstalk in cancer. Cytokine & growth factor reviews 21: 11–19. 59. Syed DN, Afaq F, Kweon MH, Hadi N, Bhatia N, et al. (2006) Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-[kappa]B activation in normal human bronchial epithelial cells. Oncogene 26: 673–682. 60. Ahmad N, Cheng P, Mukhtar H (2000) Cell Cycle Dysregulation by Green Tea Polyphenol Epigallocatechin-3-Gallate. Biochemical and Biophysical Research Communications 275: 328–334. 61. Balasubramanian S, Adhikary G, Eckert RL (2010) The Bmi-1 polycomb protein antagonizes the (2)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival. Carcinogenesis 31: 496–503. 62. Ahmad N, Gupta S, Mukhtar H (2000) Green Tea Polyphenol Epigallocatechin- 3-Gallate Differentially Modulates Nuclear Factor [kappa]B in Cancer Cells versus Normal Cells. Archives of Biochemistry and Biophysics 376: 338–346. 63. Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, et al. (2006) Suppression of Wnt Signaling by the Green Tea Compound (2)-Epigalloca- techin 3-Gallate (EGCG) in Invasive Breast Cancer Cells. Journal of Biological Chemistry 281: 10865–10875. 64. Siegelin MD, Habel A, Gaiser T (2008) Epigalocatechin-3-gallate (EGCG) downregulates PEA15 and thereby augments TRAIL-mediated apoptosis in malignant glioma. Neuroscience Letters 448: 161–165. 65. Liau S-S, Whang E (2008) HMGA1 Is a Molecular Determinant of Chemoresistance to Gemcitabine in Pancreatic Adenocarcinoma. Clinical Cancer Research 14: 1470–1477. 66. Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, et al. (2010) Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J Mol Biol 400: 413–433. 67. Cooper JE, Wiseman AC (2010) Novel immunosuppressive agents in kidney transplantation. Clin Nephrol 73: 333–343. 68. Konoeda F, Shichita T, Yoshida H, Sugiyama Y, Muto G, et al. (2010) Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model. Biochem Biophys Res Commun 402: 500–506. 69. Park HB, Oh K, Garmaa N, Seo MW, Byoun OJ, et al. (2010) CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-cell-mediated acute graft-versus-host disease by inhibiting the interferon-gamma pathway. Transplantation 90: 825–835. 70. Tak PP, Kalden JR (2011) Advances in rheumatology: new targeted therapeutics. Arthritis Res Ther 13 Suppl 1: S5. 71. West K (2009) CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs 10: 491–504. 72. Borie DC, Si MS, Morris RE, Reitz BA, Changelian PS (2003) JAK3 inhibition as a new concept for immune suppression. Curr Opin Investig Drugs 4: 1297–1303. PLoS ONE | www.plosone.org 11 February 2012 | Volume 7 | Issue 2 | e31067