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Therapeutic modulators of STAT signalling for human diseases

Nature Reviews Drug Discovery volume 12, pages611–629(2013)Cite this article

Subjects

Key Points

  • Considerable evidence supports the crucial roles of the signal transducer and activator of transcription (STAT) family of proteins in human diseases, particularly in immune and inflammatory disorders, infection and cancer

  • Increasing emphasis is being placed on developing direct STAT inhibitors for clinical application, mainly through the discovery of small molecules, oligonucleotides and natural product derivatives.

  • A large part of the ongoing STATs drug discovery research for therapeutics is focused on targeting STAT3, of which the efforts to develop small-molecule STAT3 inhibitors is extensive. While research into oligodeoxynucleotide (ODN) decoys and antisense oligonucleotides (ASOs) as STAT-inhibitory approaches is not as widespread, these efforts appear to be advancing as a STAT3 ODN has progressed to clinical trials (Phase 0).

  • Tyrosine kinase inhibitors (TKIs) as therapeutic modalities are widely explored, and this approach is highly established. TKI agents may be therapeutic considerations in STAT-associated diseases in so far as a causal link could be established between the target tyrosine kinase and dysregulated STAT signalling that is prevalent in the disease.

  • The precedence of natural product-based therapeutics for many diseases and the number of reports on natural product inhibitors of STAT3 signalling together highlight the potential of this resource as an important source of leads for developing STAT inhibitors.

  • There is a clinical trial to evaluate ISIS-STAT3Rx ASO against advanced cancers. Other clinical trials are focusing on therapeutic modalities that can affect STAT function and STAT-associated diseases, including the evaluation of curcumin for pancreatic cancer, resveratrol for colorectal cancer and 3,3′-diindolylmethane for breast cancer, and TKIs against many cancer types.

Abstract

The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.

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Figure 1: A schematic representation of the structures of the STAT proteins.
Figure 2: STAT signalling pathway, functions and associated diseases.
Figure 3: Models of inhibition of STAT signalling.

References

  1. 1

    Bromberg, J. & Darnell, J. E. Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468–2473 (2000).

    CAS  PubMed  Google Scholar 

  2. 2

    Darnell, J. E. Jr. STATs and gene regulation. Science 277, 1630–1635 (1997).

    CAS  PubMed  Google Scholar 

  3. 3

    Stark, G. R. & Darnell, J. E. Jr. The JAK–STAT pathway at twenty. Immunity 36, 503–514 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Adamkova, L., Souckova, K. & Kovarik, J. Transcription protein STAT1: biology and relation to cancer. Folia Biol. 53, 1–6 (2007).

    CAS  Google Scholar 

  5. 5

    Szabo, S. J. et al. Molecular mechanisms regulating Th1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).

    CAS  PubMed  Google Scholar 

  6. 6

    Meraz, M. A. et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK–STAT signaling pathway. Cell 84, 431–442 (1996).

    CAS  PubMed  Google Scholar 

  7. 7

    Agrawal, S. et al. Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development. Circulation 115, 2939–2947 (2007).

    CAS  PubMed  Google Scholar 

  8. 8

    Liu, L. et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208, 1635–1648 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    van de Veerdonk, F. L. et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011).

    CAS  PubMed  Google Scholar 

  10. 10

    Gamero, A. M. et al. STAT2 contributes to promotion of colorectal and skin carcinogenesis. Cancer Prev. Res. 3, 495–504 (2010).

    CAS  Google Scholar 

  11. 11

    Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl Acad. Sci. USA 94, 3801–3804 (1997).

    CAS  PubMed  Google Scholar 

  12. 12

    Akira, S. Functional roles of STAT family proteins: lessons from knockout mice. Stem Cells 17, 138–146 (1999). A comprehensive review of the knowledge gained from STAT-knockout mice.

    CAS  PubMed  Google Scholar 

  13. 13

    Takeda, K. et al. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161, 4652–4660 (1998).

    CAS  PubMed  Google Scholar 

  14. 14

    Sano, S. et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 18, 4657–4668 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Macias, E., Rao, D. & Digiovanni, J. Role of STAT3 in skin carcinogenesis: insights gained from relevant mouse models. J. Skin Cancer 2013, 684050 (2013).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Bowman, T. et al. STATs in oncogenesis. Oncogene 19, 2474–2488 (2000).

    CAS  PubMed  Google Scholar 

  17. 17

    Darnell, J. E. Validating Stat3 in cancer therapy. Nature Med. 11, 595–596 (2005).

    CAS  PubMed  Google Scholar 

  18. 18

    Jing, N. & Tweardy, D. J. Targeting Stat3 in cancer therapy. Anticancer Drugs 16, 601–607 (2005).

    CAS  PubMed  Google Scholar 

  19. 19

    Yu, H. & R. Jove, The STATs of cancer — new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).

    CAS  Google Scholar 

  20. 20

    Buettner, R., Mora, L. B. & Jove, R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer Res. 8, 945–954 (2002).

    CAS  PubMed  Google Scholar 

  21. 21

    Turkson, J. & Jove, R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19, 6613–6626 (2000).

    CAS  PubMed  Google Scholar 

  22. 22

    Yue, P. & Turkson, J. Targeting STAT3 in cancer: how successful are we? Expert Opin. Investig. Drugs 18, 45–56 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Turkson, J. STAT proteins as novel targets for cancer drug discovery. Expert Opin. Ther. Targets. 8, 409–422 (2004).

    CAS  PubMed  Google Scholar 

  24. 24

    Kortylewski, M. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Med. 11, 1314–1321 (2005).

    CAS  PubMed  Google Scholar 

  25. 25

    Wang, T. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nature Med, 10, 48–54 (2004). This paper proves that STAT3 signalling negatively influences the antitumour activity of tumour-infiltrating immune cells.

    PubMed  Google Scholar 

  26. 26

    Siddiquee, K. et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc. Natl Acad. Sci. USA 104, 7391–7396 (2007).

    CAS  PubMed  Google Scholar 

  27. 27

    Siddiquee, K. A. et al. An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. ACS Chem. Biol. 2, 787–798 (2007).

    CAS  Google Scholar 

  28. 28

    Sen, M. et al. Lack of toxicity of a STAT3 decoy oligonucleotide. Cancer Chemother. Pharmacol. 63, 983–995 (2009).

    CAS  PubMed  Google Scholar 

  29. 29

    Niu, G. et al. Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res, 59, 5059–5063 (1999). This study demonstrates for the first time that STAT3 is a valid anticancer therapeutic target, as a dominant-negative STAT3 variant significantly inhibits tumour growth in a melanoma xenograft mouse model.

    CAS  Google Scholar 

  30. 30

    Turkson, J. et al. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem, 276, 45443–45455 (2001). This study describes the first inhibitor of a STAT protein, which is a designed peptide that can successfully suppress STAT3 signalling.

    CAS  Google Scholar 

  31. 31

    Holland, S. M. et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    Koskela, H. L. et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N. Engl. J. Med, 366, 1905–1913 (2012). This study identifies mutations within the STAT3 SH2 domain in patients with large granular lymphocytic leukaemia, causing STAT3 hyperactivation.

    CAS  Google Scholar 

  33. 33

    Mogensen, T. H., Jakobsen, M. A. & Larsen, C. S. Identification of a novel STAT3 mutation in a patient with hyper-IgE syndrome. Scand. J. Infect. Dis. 45, 235–238 (2013).

    PubMed  Google Scholar 

  34. 34

    Lovett-Racke, A. E., Yang, Y. & Racke, M. K. Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis? Biochim. Biophys. Acta 1812, 246–251 (2011).

    CAS  PubMed  Google Scholar 

  35. 35

    Chitnis, T. et al. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J. Clin. Invest. 108, 739–747 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Menke, J. et al. Targeting transcription factor Stat4 uncovers a role for interleukin-18 in the pathogenesis of severe lupus nephritis in mice. Kidney Int. 79, 452–463 (2011).

    CAS  PubMed  Google Scholar 

  37. 37

    Lin, J. X. & Leonard, W. J. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19, 2566–2576 (2000).

    CAS  PubMed  Google Scholar 

  38. 38

    Buitenhuis, M. et al. Signal transducer and activator of transcription 5a (STAT5a) is required for eosinophil differentiation of human cord blood-derived CD34+ cells. Blood. 101, 134–142 (2003).

    CAS  PubMed  Google Scholar 

  39. 39

    Udy, G. B. et al. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc. Natl Acad. Sci. USA 94, 7239–7244 (1997).

    CAS  PubMed  Google Scholar 

  40. 40

    Imada, K. et al. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med. 188, 2067–2074 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Nelson, E. A. et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood 117, 3421–3429 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Cotarla, I. et al. Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers. Int. J. Cancer 108, 665–671 (2004).

    CAS  PubMed  Google Scholar 

  43. 43

    Shuai, K. et al. Constitutive activation of STAT5 by the BCR–ABL oncogene in chronic myelogenous leukemia. Oncogene 13, 247–254 (1996).

    CAS  PubMed  Google Scholar 

  44. 44

    Benekli, M., Baumann, H. & Wetzler, M. Targeting signal transducer and activator of transcription signaling pathway in leukemias. J. Clin. Oncol. 27, 4422–4432 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Nelson, E. A. et al. A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotarget 2, 518–524 (2011).

    PubMed  PubMed Central  Google Scholar 

  46. 46

    Hou, J. et al. An interleukin-4-induced transcription factor: IL-4 Stat. Science 265, 1701–1706 (1994).

    CAS  PubMed  Google Scholar 

  47. 47

    Sehra, S. et al. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J. Immunol. 184, 3186–3190 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Chapoval, S. P. et al. STAT6 expression in multiple cell types mediates the cooperative development of allergic airway disease. J. Immunol. 186, 2571–2583 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Kuperman, D. A. & Schleimer, R. P. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr. Mol. Med. 8, 384–392 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Chiba, Y. et al. Interleukin-13 augments bronchial smooth muscle contractility with an up-regulation of RhoA protein. Am. J. Respir. Cell. Mol. Biol. 40, 159–167 (2009).

    CAS  PubMed  Google Scholar 

  51. 51

    Chiba, Y. et al. A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. Am. J. Respir. Cell. Mol. Biol. 41, 516–524 (2009).

    CAS  PubMed  Google Scholar 

  52. 52

    Khaled, W. T. et al. The IL-4/IL-13/Stat6 signaling pathway promotes luminal mammary epithelial cell development. Development 134, 2739–2750 (2007).

    CAS  PubMed  Google Scholar 

  53. 53

    O'Shea, J. J., Holland, S. M. & Staudt, L. M. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med. 368, 161–170 (2013).

    CAS  PubMed  Google Scholar 

  54. 54

    Quintas-Cardama, A. & Verstovsek, S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin. Cancer Res. 19, 1933–1940 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Turkson, J. et al. Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol. Cancer Ther. 3, 261–269 (2004).

    CAS  PubMed  Google Scholar 

  56. 56

    Coleman, D. R. et al. Investigation of the binding determinants of phosphopeptides targeted to the SRC homology 2 domain of the signal transducer and activator of transcription 3. Development of a high-affinity peptide inhibitor. J. Med. Chem. 48, 6661–6670 (2005).

    CAS  PubMed  Google Scholar 

  57. 57

    Ren, Z. et al. Identification of a high-affinity phosphopeptide inhibitor of Stat3. Bioorg. Med. Chem. Lett. 13, 633–636 (2003).

    CAS  PubMed  Google Scholar 

  58. 58

    Gunning, P. T. et al. Isoform selective inhibition of STAT1 or STAT3 homo-dimerization via peptidomimetic probes: structural recognition of STAT SH2 domains. Bioorg. Med. Chem. Lett. 17, 1875–1878 (2007).

    CAS  PubMed  Google Scholar 

  59. 59

    McMurray, J. S., Structural basis for the binding of high affinity phosphopeptides to Stat3. Biopolymers 90, 69–79 (2008).

    CAS  PubMed  Google Scholar 

  60. 60

    Zhao, W. Jaganathan, S. & Turkson, J. A cell-permeable Stat3 SH2 domain mimetic inhibits Stat3 activation and induces antitumor cell effects in vitro. J. Biol. Chem. 285, 35855–35865 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Chen, J. et al. Structure-based design of conformationally constrained, cell-permeable STAT3 inhibitors. ACS Med. Chem. Lett. 1, 85–89 (2010).

    Google Scholar 

  62. 62

    Mandal, P. K. et al. Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3. J. Med. Chem. 54, 3549–3563 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Auzenne, E. J. et al. A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis. J. Exp. Ther. Oncol. 10, 155–162 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Song, H. et al. A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc. Natl Acad. Sci. USA 102, 4700–4705 (2005).

    CAS  PubMed  Google Scholar 

  65. 65

    Fuh, B. et al. LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. Br. J. Cancer 100, 106–112 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Hao, W. et al. Discovery of the catechol structural moiety as a Stat3 SH2 domain inhibitor by virtual screening. Bioorg. Med. Chem. Lett. 18, 4988–4992 (2008).

    CAS  PubMed  Google Scholar 

  67. 67

    Zhang, X. et al. A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem. Pharmacol. 79, 1398–1409 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Zhang, X. et al. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc. Natl Acad. Sci. USA 109, 9623–9628 (2012).

    CAS  PubMed  Google Scholar 

  69. 69

    Zhang, X. et al. A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation. Cancer Res. 73, 1922–1933 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Xu, X. et al. Chemical probes that competitively and selectively inhibit Stat3 activation. PLoS ONE 4, e4783 (2009).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Dave, B. et al. Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model. PLoS ONE 7, e30207 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Schust, J. et al. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 13, 1235–1242 (2006).

    CAS  Google Scholar 

  73. 73

    Ashizawa, T. et al. Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation. Int. J. Oncol. 38, 1245–1252 (2011).

    CAS  PubMed  Google Scholar 

  74. 74

    Matsuno, K. et al. Identification of a new series of STAT3 inhibitors by virtual screening. ACS Med. Chem. Lett. 1, 371–3755 (2010).

    CAS  Google Scholar 

  75. 75

    Chen, H. et al. Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy. Eur. J. Med. Chem. 62C, 498–507 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Zhang, M. et al. Identification and characterization of small molecule inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening. Bioorg. Med. Chem. Lett. 23, 2225–2229 (2013).

    CAS  PubMed  Google Scholar 

  77. 77

    Kim, M. J. et al. OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells. Cancer Lett. 335, 145–152 (2013).

    CAS  PubMed  Google Scholar 

  78. 78

    Yang, C. L. et al. Curcumin blocks small cell lung cancer cells migration, invasion, angiogenesis, cell cycle and neoplasia through Janus kinase–STAT3 signaling pathway. PLoS ONE 7, e37960 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Tu, S. P. et al. Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer Prev. Res. 5, 205–215 (2012).

    CAS  Google Scholar 

  80. 80

    Fossey, S. L. et al. The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines. BMC Cancer 11, 112 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Selvendiran, K. et al. HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition. Cancer Biol. Ther. 12, 837–845 (2011).

    CAS  PubMed  Google Scholar 

  82. 82

    Tierney, B. J. et al. HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells. Cancer Biol. Ther. 13, 766–775 (2012).

    CAS  PubMed  Google Scholar 

  83. 83

    Lin, L. et al. Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res. 70, 2445–2454 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Onimoe, G. I. et al. Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice. Invest. New Drugs 30, 916–926 (2012).

    CAS  PubMed  Google Scholar 

  85. 85

    Bid, H. K. et al. Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12. PLoS ONE 7, e35513 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Lin, L. et al. A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells. Mol. Cancer 9, 217 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Bill, M. A. et al. Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines. PLoS ONE 7, e40724 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Nam, S. et al. Novel synthetic derivatives of the natural product berbamine inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells. Mol. Oncol. 6, 484–493 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Zhang, X. et al. Indirubin inhibits tumor growth by antitumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell. Int. J. Cancer 129, 2502–2511 (2011).

    CAS  PubMed  Google Scholar 

  90. 90

    Nam, S. et al. Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells. Proc. Natl Acad. Sci. USA 102, 5998–6003 (2005).

    CAS  PubMed  Google Scholar 

  91. 91

    Liu, L. et al. A novel 7-bromoindirubin with potent anticancer activity suppresses survival of human melanoma cells associated with inhibition of STAT3 and Akt signaling. Cancer Biol. Ther. 13, 13 (2012).

    CAS  Google Scholar 

  92. 92

    Nam, S. et al. Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells. Mol. Oncol. 7, 369–378 (2013).

    CAS  PubMed  Google Scholar 

  93. 93

    Shakibaei, M., Harikumar, K. B. & Aggarwal, B. B. Resveratrol addiction: to die or not to die. Mol. Nutr. Food Res. 53, 115–128 (2009).

    CAS  PubMed  Google Scholar 

  94. 94

    Li, T. et al. Evaluation of anti-leukemia effect of resveratrol by modulating STAT3 signaling. Int. Immunopharmacol. 10, 18–25 (2010).

    CAS  PubMed  Google Scholar 

  95. 95

    Kim, J. E. et al. LYR71, a derivative of trimeric resveratrol, inhibits tumorigenesis by blocking STAT3-mediated matrix metalloproteinase 9 expression. Exp. Mol. Med. 40, 514–522 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Yang, Y. P. et al. Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis. J. Cell. Physiol. 227, 976–993 (2012).

    CAS  PubMed  Google Scholar 

  97. 97

    Gupta, S. C. et al. Chemosensitization of tumors by resveratrol. Ann. NY Acad. Sci. 1215, 150–160 (2011).

    CAS  PubMed  Google Scholar 

  98. 98

    Piotrowska, H. Kucinska, M. & Murias, M. Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat. Res. 750, 60–82 (2012).

    CAS  PubMed  Google Scholar 

  99. 99

    Santandreu, F. M. et al. Resveratrol potentiates the cytotoxic oxidative stress induced by chemotherapy in human colon cancer cells. Cell Physiol. Biochem. 28, 219–228 (2011).

    CAS  PubMed  Google Scholar 

  100. 100

    Lin, C. L. et al. Protective effect of caffeic acid on paclitaxel induced anti-proliferation and apoptosis of lung cancer cells involves NF-κB pathway. Int. J. Mol. Sci. 13, 6236–6245 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Jung, J. E. et al. Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells. Carcinogenesis 28, 1780–1787 (2007).

    CAS  PubMed  Google Scholar 

  102. 102

    Kong, L. Y. et al. Inhibition of p-STAT3 enhances IFN-α efficacy against metastatic melanoma in a murine model. Clin. Cancer Res. 16, 2550–2561 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Sai, K. et al. Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway. J. Neurooncol. 107, 487–501 (2012).

    CAS  PubMed  Google Scholar 

  104. 104

    Lee, H. K. et al. Capsaicin inhibits the IL-6/STAT3 pathway by depleting intracellular gp130 pools through endoplasmic reticulum stress. Biochem. Biophys. Res. Commun. 382, 445–450 (2009).

    CAS  PubMed  Google Scholar 

  105. 105

    Shin, D. S. et al. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res. 69, 193–202 (2009).

    CAS  PubMed  Google Scholar 

  106. 106

    Walker, S. R. et al. Microtubule-targeted chemotherapeutic agents inhibit signal transducer and activator of transcription 3 (STAT3) signaling. Mol. Pharmacol. 78, 903–908 (2010).

    CAS  PubMed  Google Scholar 

  107. 107

    Kannaiyan, R. et al. Celastrol inhibits proliferation and induces chemosensitization through down-regulation of NF-κB and STAT3 regulated gene products in multiple myeloma cells. Br. J. Pharmacol. 164, 1506–1521 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Rajendran, P. et al. Celastrol suppresses growth and induces apoptosis of human hepatocellular carcinoma through the modulation of STAT3/JAK2 signaling cascade in vitro and in vivo. Cancer Prev. Res. 5, 631–643 (2012).

    CAS  Google Scholar 

  109. 109

    Zhang, C. et al. Avicin D selectively induces apoptosis and downregulates p-STAT-3, BCL-2, and survivin in cutaneous T-cell lymphoma cells. J. Invest. Dermatol. 128, 2728–2735 (2008).

    CAS  PubMed  Google Scholar 

  110. 110

    Lee, J., Hahm, E. R. & Singh, S. V. Withaferin A inhibits activation of signal transducer and activator of transcription3 in human breast cancer cells. Carcinogenesis 31, 1991–1998 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Um, H. J. et al. Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem. Biophys. Res. Commun. 427, 24–29 (2012).

    CAS  PubMed  Google Scholar 

  112. 112

    Pandey, M. K., Sung, B. & Aggarwal, B. B. Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. Int. J. Cancer 127, 282–292 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Pathak, A. K. et al. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol. Cancer Res. 5, 943–955 (2007).

    CAS  PubMed  Google Scholar 

  114. 114

    Shanmugam, M. K. et al. Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice. J. Mol. Med. 89, 713–727 (2011).

    CAS  PubMed  Google Scholar 

  115. 115

    Honda, T. et al. Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages. J. Med. Chem. 43, 4233–4246 (2000).

    CAS  PubMed  Google Scholar 

  116. 116

    Duan, Z. et al. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother. Pharmacol. 63, 681–689 (2009).

    CAS  PubMed  Google Scholar 

  117. 117

    Ryu, K. et al. Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway. BMC Cancer 10, 187 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Tran, K. et al. The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice. Cancer Prev. Res. 5, 726–734 (2012).

    CAS  Google Scholar 

  119. 119

    Blaskovich, M. A. et al. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res. 63, 1270–1279 (2003).

    CAS  PubMed  Google Scholar 

  120. 120

    Hsu, H. S. et al. Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells. Cancer 117, 2970–2985 (2011).

    CAS  PubMed  Google Scholar 

  121. 121

    Chang, C. J. et al. Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells. Childs Nerv. Syst. 28, 363–373 (2012).

    Google Scholar 

  122. 122

    Tseng, L. M. et al. Targeting signal transducer and activator of transcription 3 pathway by cucurbitacin I diminishes self-renewing and radiochemoresistant abilities in thyroid cancer-derived CD133+ cells. J. Pharmacol. Exp. Ther. 341, 410–423 (2012).

    CAS  PubMed  Google Scholar 

  123. 123

    Liu, T. et al. Cucurbitacin B, a small molecule inhibitor of the Stat3 signaling pathway, enhances the chemosensitivity of laryngeal squamous cell carcinoma cells to cisplatin. Eur. J. Pharmacol. 641, 15–22 (2010).

    CAS  PubMed  Google Scholar 

  124. 124

    Dong, Y. et al. Cucurbitacin E, a tetracyclic triterpenes compound from Chinese medicine, inhibits tumor angiogenesis through VEGFR2-mediated Jak2–STAT3 signaling pathway. Carcinogenesis 31, 2097–2104 (2010).

    CAS  PubMed  Google Scholar 

  125. 125

    Sun, C. et al. Inhibitory effect of cucurbitacin E on pancreatic cancer cells growth via STAT3 signaling. J. Cancer Res. Clin. Oncol. 136, 603–610 (2010).

    CAS  PubMed  Google Scholar 

  126. 126

    Huang, W. W. et al. Cucurbitacin E induces G(2)/M phase arrest through STAT3/p53/p21 signaling and provokes apoptosis via Fas/CD95 and mitochondria-dependent pathways in human bladder cancer T24 cells. Evid. Based. Complement. Alternat. Med. 2012, 952762 (2012).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Li, F. et al. Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells. Cancer Lett. 292, 197–207 (2010).

    CAS  PubMed  Google Scholar 

  128. 128

    Muto, A. et al. Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor. Mol. Cancer Ther. 6, 987–994 (2007).

    CAS  PubMed  Google Scholar 

  129. 129

    Badr, G., Mohany, M. & Abu-Tarboush, F. Thymoquinone decreases F-actin polymerization and the proliferation of human multiple myeloma cells by suppressing STAT3 phosphorylation and Bcl2/Bcl-XL expression. Lipids Health Dis. 10, 236 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Li, F., Rajendran, P. & Sethi, G. Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway. Br. J. Pharmacol. 161, 541–554 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Leeman-Neill, R. J. et al. Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors. Clin. Cancer Res. 16, 2571–2579 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Rajendran, P. et al. Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1. J. Cell. Physiol. 227, 2184–2195 (2012).

    CAS  PubMed  Google Scholar 

  133. 133

    Liu, S. H. et al. Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice. PLoS ONE 7, e43711 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Yang, J. et al. Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells. Cancer Lett. 325, 243–251 (2013).

    Google Scholar 

  135. 135

    Arbiser, J. L. et al. Carbazole is a naturally occurring inhibitor of angiogenesis and inflammation isolated from antipsoriatic coal tar. J. Invest. Dermatol. 126, 1396–1402 (2006).

    CAS  PubMed  Google Scholar 

  136. 136

    Saturnino, C. et al. Synthesis and biological evaluation of new N-alkylcarbazole derivatives as STAT3 inhibitors: preliminary study. Eur. J. Med. Chem. 60C, 112–119 (2012).

    CAS  PubMed  Google Scholar 

  137. 137

    Sun, M. et al. Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate 72, 82–89 (2012).

    CAS  PubMed  Google Scholar 

  138. 138

    Kannappan, R., Yadav, V. R. & Aggarwal, B. B. γ-Tocotrienol but not γ-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents. J. Biol. Chem. 285, 33520–33528 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Rajendran, P. et al. γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signaling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent. Br. J. Pharmacol. 163, 283–298 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Kunnumakkara, A. B. et al. Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol. Cancer Res. 7, 118–128 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Kandala, P. K. & Srivastava, S. K. Regulation of Janus-activated kinase-2 (JAK2) by diindolylmethane in ovarian cancer in vitro and in vivo. Drug Discov. Ther. 6, 94–101 (2012).

    CAS  PubMed  Google Scholar 

  142. 142

    Chen, X. et al. Brevilin A, a novel natural product, inhibits Janus kinase activity and blocks STAT3 signaling in cancer cells. PLoS ONE 8, e63697 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Leon, M. L. & Zuckerman, S. H. Gamma interferon: a central mediator in atherosclerosis. Inflamm. Res. 54, 395–411 (2005).

    CAS  PubMed  Google Scholar 

  144. 144

    Zhou, X. X., Gao, P. J. & Sun, B. G. Pravastatin attenuates interferon-γ action via modulation of STAT1 to prevent aortic atherosclerosis in apolipoprotein E-knockout mice. Clin. Exp. Pharmacol. Physiol. 36, 373–379 (2009).

    CAS  PubMed  Google Scholar 

  145. 145

    Ren, Y. et al. Novel immunomodulatory properties of berbamine through selective down-regulation of STAT4 and action of IFN-γ in experimental autoimmune encephalomyelitis. J. Immunol. 181, 1491–1498 (2008).

    CAS  PubMed  Google Scholar 

  146. 146

    Nagelkerken, L. Role of Th1 and Th2 cells in autoimmune demyelinating disease. Braz. J. Med. Biol. Res. 31, 55–60 (1998).

    CAS  PubMed  Google Scholar 

  147. 147

    Lee, B. J. et al. Immunomodulatory effect of water extract of cinnamon on anti-CD3-induced cytokine responses and p38, JNK, ERK1/2, and STAT4 activation. Immunopharmacol. Immunotoxicol. 33, 714–722 (2011).

    CAS  PubMed  Google Scholar 

  148. 148

    Madan, E. et al. Regulation of apoptosis by resveratrol through JAK/STAT and mitochondria mediated pathway in human epidermoid carcinoma A431 cells. Biochem. Biophys. Res. Commun. 377, 1232–1237 (2008).

    CAS  PubMed  Google Scholar 

  149. 149

    Muller, J. et al. Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem 9, 723–727 (2008).

    PubMed  Google Scholar 

  150. 150

    Nam, S. et al. Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol. Oncol. 6, 276–283 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Stolzenberger, S. Haake, M. & Duschl, A. Specific inhibition of interleukin-4-dependent Stat6 activation by an intracellularly delivered peptide. Eur. J. Biochem. 268, 4809–4814 (2001).

    CAS  PubMed  Google Scholar 

  152. 152

    McCusker, C. T. et al. Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT-6 peptide. J. Immunol. 179, 2556–2564 (2007).

    CAS  PubMed  Google Scholar 

  153. 153

    Wang, Y. et al. Effective treatment of experimental ragweed-induced asthma with STAT-6-IP, a topically delivered cell-penetrating peptide. Clin. Exp. Allergy 41, 1622–1630 (2011).

    CAS  PubMed  Google Scholar 

  154. 154

    Sakurai, M. et al. TMC-264, a novel inhibitor of STAT6 activation produced by Phoma sp. TC 1674. J. Antibiot. 56, 513–519 (2003).

    CAS  PubMed  Google Scholar 

  155. 155

    Nagashima, S. et al. Identification of 4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide derivatives as potent and orally bioavailable STAT6 inhibitors. Bioorg. Med. Chem. 16, 6509–6521 (2008).

    CAS  PubMed  Google Scholar 

  156. 156

    Nagashima, S. et al. Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors. Bioorg. Med. Chem. 17, 6926–6936 (2009).

    CAS  PubMed  Google Scholar 

  157. 157

    Nakano, T. et al. Niflumic acid suppresses interleukin-13-induced asthma phenotypes. Am. J. Respir. Crit. Care Med. 173, 1216–1221 (2006).

    CAS  PubMed  Google Scholar 

  158. 158

    Zhou, L. et al. STAT6 phosphorylation inhibitors block eotaxin-3 secretion in bronchial epithelial cells. Bioorg. Med. Chem. 20, 750–758 (2012).

    CAS  PubMed  Google Scholar 

  159. 159

    Manshouri, T. et al. Bone marrow stroma-secreted cytokines protect JAK2(V617F)-mutated cells from the effects of a JAK2 inhibitor. Cancer Res. 71, 3831–3840 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Quintas-Cardama, A. et al. Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor. Invest. New Drugs 29, 818–826 (2011).

    CAS  PubMed  Google Scholar 

  161. 161

    Kantarjian, H. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 362, 2260–2270 (2010).

    CAS  PubMed  Google Scholar 

  162. 162

    Duensing, A. et al. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23, 3999–4006 (2004).

    CAS  PubMed  Google Scholar 

  163. 163

    Ravandi, F. et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 116, 2070–2077 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Nam, S. et al. Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Mol. Cancer Ther. 6, 1400–1405 (2007).

    CAS  PubMed  Google Scholar 

  165. 165

    Quentmeier, H. et al. BCR–ABL1-independent PI3Kinase activation causing imatinib-resistance. J. Hematol. Oncol. 4, 6 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Pallis, A. G. & Syrigos, K. N. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC. Lung Cancer 80, 120–130 (2013).

    CAS  PubMed  Google Scholar 

  167. 167

    Leeman-Neill, R. J. et al. Inhibition of EGFR–STAT3 signaling with erlotinib prevents carcinogenesis in a chemically-induced mouse model of oral squamous cell carcinoma. Cancer Prev. Res. (Phila) 4, 230–237 (2011).

    CAS  Google Scholar 

  168. 168

    Bachawal, S. V., Wali, V. B. & Sylvester, P. W. Combined γ-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells. Anticancer Res. 30, 429–437 (2010).

    CAS  Google Scholar 

  169. 169

    Cheng, A. L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2009).

    CAS  PubMed  Google Scholar 

  170. 170

    Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    CAS  PubMed  Google Scholar 

  171. 171

    Yang, Y. et al. The monoclonal antibody CH12 enhances the sorafenib-mediated growth inhibition of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III. Neoplasia 14, 509–518 (2012).

    PubMed  PubMed Central  Google Scholar 

  172. 172

    Yang, F. et al. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol. Cancer Ther. 9, 953–962 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Yang, F. et al. Sorafenib inhibits endogenous and IL-6/S1P induced JAK2–STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis. Cancer Biol. Ther. 13, 534–541 (2012).

    CAS  PubMed  Google Scholar 

  174. 174

    Tai, W. T. et al. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J. Hepatol. 55, 1041–1048 (2011).

    CAS  PubMed  Google Scholar 

  175. 175

    Chen, K. F. et al. Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody. Br. J. Pharmacol. 168, 658–672 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Chen, K. F. et al. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur. J. Med. Chem. 55, 220–227 (2012).

    CAS  PubMed  Google Scholar 

  177. 177

    Pedranzini, L. et al. Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res. 66, 9714–9721 (2006).

    CAS  PubMed  Google Scholar 

  178. 178

    Nelson, E. A. et al. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood 112, 5095–5102 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Muhammad, S. et al. The role of EGFR monoclonal antibodies (MoABs) cetuximab/panitumab, and BRAF inhibitors in BRAF mutated colorectal cancer. J. Gastrointest Oncol. 4, 72–81 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Patel, D. et al. Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation. Int. J. Oncol. 34, 25–32 (2009).

    CAS  PubMed  Google Scholar 

  181. 181

    Gravalos, C. et al. Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer. Clin. Transl. Oncol. 13, 179–184 (2011).

    CAS  PubMed  Google Scholar 

  182. 182

    Kim, S. Y. et al. Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. Int. J. Oncol. 32, 89–95 (2008).

    PubMed  Google Scholar 

  183. 183

    Migita, K. et al. Inhibitory effects of the JAK inhibitor CP690,550 on human CD4+ T lymphocyte cytokine production. BMC Immunol. 12, 51 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Quintas-Cardama, A. et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115, 3109–3117 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    Looyenga, B. D. et al. STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma. PLoS ONE 7, e30820 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Derenzini, E. et al. The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. Blood Cancer J. 1, e46 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Hedvat, M. et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 16, 487–497 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    McFarland, B. C. et al. Therapeutic potential of AZD1480 for the treatment of human glioblastoma. Mol. Cancer Ther. 10, 2384–2393 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Xin, H. et al. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res. 71, 6601–6610 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Faderl, S. et al. Atiprimod blocks phosphorylation of JAK–STAT and inhibits proliferation of acute myeloid leukemia (AML) cells. Leuk. Res. 31, 91–95 (2007).

    CAS  PubMed  Google Scholar 

  191. 191

    Amit-Vazina, M. et al. Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells. Br. J. Cancer. 93, 70–80 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Kim, N. H. et al. Auranofin blocks interleukin-6 signaling by inhibiting phosphorylation of JAK1 and STAT3. Immunology 122, 607–614 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Nakaya, A. et al. The gold compound auranofin induces apoptosis of human multiple myeloma cells through both down-regulation of STAT3 and inhibition of NF-κB activity. Leuk. Res. 35, 243–249 (2011).

    CAS  PubMed  Google Scholar 

  194. 194

    Song, L. et al. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res. 66, 5542–5548 (2006).

    CAS  PubMed  Google Scholar 

  195. 195

    Song, L. et al. JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol. Cancer Ther. 10, 481–494 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Sen, M. et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov. 2, 694–705 (2012). This is the first-in-human study of a STAT3-selective inhibitor, which is a transcription factor decoy.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Souissi, I. et al. A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line. Mol. Cancer 11, 12 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Huckel, M. et al. Attenuation of murine antigen-induced arthritis by treatment with a decoy oligodeoxynucleotide inhibiting signal transducer and activator of transcription-1 (STAT-1). Arthritis Res. Ther. 8, R17 (2006).

    PubMed  Google Scholar 

  199. 199

    Stadlbauer, T. H. et al. AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts. Cardiovasc. Res. 79, 698–705 (2008).

    CAS  PubMed  Google Scholar 

  200. 200

    Wang, X. et al. Targeted blockage of signal transducer and activator of transcription 5 signaling pathway with decoy oligodeoxynucleotides suppresses leukemic K562 cell growth. DNA Cell Biol. 30, 71–78 (2011).

    PubMed  PubMed Central  Google Scholar 

  201. 201

    Shen, J., Li, R. & Li, G. Inhibitory effects of decoy-ODN targeting activated STAT3 on human glioma growth in vivo. In Vivo 23, 237–243 (2009).

    CAS  PubMed  Google Scholar 

  202. 202

    Sen, M. et al. Targeting Stat3 abrogates EGFR inhibitor resistance in cancer. Clin. Cancer Res. 18, 4986–4996 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Lui, V. W. et al. Antiproliferative mechanisms of a transcription factor decoy targeting signal transducer and activator of transcription (STAT) 3: the role of STAT1. Mol. Pharmacol. 71, 1435–1443 (2007).

    CAS  PubMed  Google Scholar 

  204. 204

    Niu, G. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008 (2002).

    CAS  PubMed  Google Scholar 

  205. 205

    Barton, B. E. et al. Novel single-stranded oligonucleotides that inhibit signal transducer and activator of transcription 3 induce apoptosis in vitro and in vivo in prostate cancer cell lines. Mol. Cancer Ther. 3, 1183–1191 (2004).

    CAS  PubMed  Google Scholar 

  206. 206

    Li, W. C. et al. Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin. Cancer Res. 12, 7140–7148 (2006).

    CAS  PubMed  Google Scholar 

  207. 207

    Burel, S. A. et al. Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid. Ther. 23, 213–227 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank all their colleagues and members of their laboratory for the stimulating discussions related to this work. The authors also thank A. Chelsky for the art work for figure 3. This work was supported by grants from the National Cancer Institute (CA128865 and CA161931) and from the University of Hawaii to J.T.

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  1. Gabriella Miklossy and Tyvette S. Hilliard: These authors contributed equally to this work.

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  1. Cancer Biology, and Natural Products and Experimental Therapeutics Programs, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, 96813, Hawaii, USA

    Gabriella Miklossy, Tyvette S. Hilliard & James Turkson

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  1. Gabriella Miklossy
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Correspondence to James Turkson.

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Miklossy, G., Hilliard, T. & Turkson, J. Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov 12, 611–629 (2013). https://doi.org/10.1038/nrd4088

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