Key Points
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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
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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.
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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).
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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.
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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.
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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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References
Bromberg, J. & Darnell, J. E. Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468–2473 (2000).
Darnell, J. E. Jr. STATs and gene regulation. Science 277, 1630–1635 (1997).
Stark, G. R. & Darnell, J. E. Jr. The JAK–STAT pathway at twenty. Immunity 36, 503–514 (2012).
Adamkova, L., Souckova, K. & Kovarik, J. Transcription protein STAT1: biology and relation to cancer. Folia Biol. 53, 1–6 (2007).
Szabo, S. J. et al. Molecular mechanisms regulating Th1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).
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).
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).
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).
van de Veerdonk, F. L. et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011).
Gamero, A. M. et al. STAT2 contributes to promotion of colorectal and skin carcinogenesis. Cancer Prev. Res. 3, 495–504 (2010).
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).
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.
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).
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).
Macias, E., Rao, D. & Digiovanni, J. Role of STAT3 in skin carcinogenesis: insights gained from relevant mouse models. J. Skin Cancer 2013, 684050 (2013).
Bowman, T. et al. STATs in oncogenesis. Oncogene 19, 2474–2488 (2000).
Darnell, J. E. Validating Stat3 in cancer therapy. Nature Med. 11, 595–596 (2005).
Jing, N. & Tweardy, D. J. Targeting Stat3 in cancer therapy. Anticancer Drugs 16, 601–607 (2005).
Yu, H. & R. Jove, The STATs of cancer — new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).
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).
Turkson, J. & Jove, R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19, 6613–6626 (2000).
Yue, P. & Turkson, J. Targeting STAT3 in cancer: how successful are we? Expert Opin. Investig. Drugs 18, 45–56 (2009).
Turkson, J. STAT proteins as novel targets for cancer drug discovery. Expert Opin. Ther. Targets. 8, 409–422 (2004).
Kortylewski, M. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Med. 11, 1314–1321 (2005).
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.
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).
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).
Sen, M. et al. Lack of toxicity of a STAT3 decoy oligonucleotide. Cancer Chemother. Pharmacol. 63, 983–995 (2009).
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.
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.
Holland, S. M. et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007).
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.
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).
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).
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).
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).
Lin, J. X. & Leonard, W. J. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19, 2566–2576 (2000).
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).
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).
Imada, K. et al. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med. 188, 2067–2074 (1998).
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).
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).
Shuai, K. et al. Constitutive activation of STAT5 by the BCR–ABL oncogene in chronic myelogenous leukemia. Oncogene 13, 247–254 (1996).
Benekli, M., Baumann, H. & Wetzler, M. Targeting signal transducer and activator of transcription signaling pathway in leukemias. J. Clin. Oncol. 27, 4422–4432 (2009).
Nelson, E. A. et al. A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotarget 2, 518–524 (2011).
Hou, J. et al. An interleukin-4-induced transcription factor: IL-4 Stat. Science 265, 1701–1706 (1994).
Sehra, S. et al. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J. Immunol. 184, 3186–3190 (2010).
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).
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).
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).
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).
Khaled, W. T. et al. The IL-4/IL-13/Stat6 signaling pathway promotes luminal mammary epithelial cell development. Development 134, 2739–2750 (2007).
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).
Quintas-Cardama, A. & Verstovsek, S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin. Cancer Res. 19, 1933–1940 (2013).
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).
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).
Ren, Z. et al. Identification of a high-affinity phosphopeptide inhibitor of Stat3. Bioorg. Med. Chem. Lett. 13, 633–636 (2003).
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).
McMurray, J. S., Structural basis for the binding of high affinity phosphopeptides to Stat3. Biopolymers 90, 69–79 (2008).
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).
Chen, J. et al. Structure-based design of conformationally constrained, cell-permeable STAT3 inhibitors. ACS Med. Chem. Lett. 1, 85–89 (2010).
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).
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).
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).
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).
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).
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).
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).
Zhang, X. et al. A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation. Cancer Res. 73, 1922–1933 (2013).
Xu, X. et al. Chemical probes that competitively and selectively inhibit Stat3 activation. PLoS ONE 4, e4783 (2009).
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).
Schust, J. et al. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 13, 1235–1242 (2006).
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).
Matsuno, K. et al. Identification of a new series of STAT3 inhibitors by virtual screening. ACS Med. Chem. Lett. 1, 371–3755 (2010).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Bid, H. K. et al. Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12. PLoS ONE 7, e35513 (2012).
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).
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).
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).
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).
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).
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).
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).
Shakibaei, M., Harikumar, K. B. & Aggarwal, B. B. Resveratrol addiction: to die or not to die. Mol. Nutr. Food Res. 53, 115–128 (2009).
Li, T. et al. Evaluation of anti-leukemia effect of resveratrol by modulating STAT3 signaling. Int. Immunopharmacol. 10, 18–25 (2010).
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).
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).
Gupta, S. C. et al. Chemosensitization of tumors by resveratrol. Ann. NY Acad. Sci. 1215, 150–160 (2011).
Piotrowska, H. Kucinska, M. & Murias, M. Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat. Res. 750, 60–82 (2012).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Yang, J. et al. Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells. Cancer Lett. 325, 243–251 (2013).
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).
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).
Sun, M. et al. Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate 72, 82–89 (2012).
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).
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).
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).
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).
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).
Leon, M. L. & Zuckerman, S. H. Gamma interferon: a central mediator in atherosclerosis. Inflamm. Res. 54, 395–411 (2005).
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).
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).
Nagelkerken, L. Role of Th1 and Th2 cells in autoimmune demyelinating disease. Braz. J. Med. Biol. Res. 31, 55–60 (1998).
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).
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).
Muller, J. et al. Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem 9, 723–727 (2008).
Nam, S. et al. Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol. Oncol. 6, 276–283 (2012).
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).
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).
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).
Sakurai, M. et al. TMC-264, a novel inhibitor of STAT6 activation produced by Phoma sp. TC 1674. J. Antibiot. 56, 513–519 (2003).
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).
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).
Nakano, T. et al. Niflumic acid suppresses interleukin-13-induced asthma phenotypes. Am. J. Respir. Crit. Care Med. 173, 1216–1221 (2006).
Zhou, L. et al. STAT6 phosphorylation inhibitors block eotaxin-3 secretion in bronchial epithelial cells. Bioorg. Med. Chem. 20, 750–758 (2012).
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).
Quintas-Cardama, A. et al. Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor. Invest. New Drugs 29, 818–826 (2011).
Kantarjian, H. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 362, 2260–2270 (2010).
Duensing, A. et al. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23, 3999–4006 (2004).
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).
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).
Quentmeier, H. et al. BCR–ABL1-independent PI3Kinase activation causing imatinib-resistance. J. Hematol. Oncol. 4, 6 (2011).
Pallis, A. G. & Syrigos, K. N. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC. Lung Cancer 80, 120–130 (2013).
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).
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).
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).
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
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).
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).
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).
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).
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).
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).
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).
Nelson, E. A. et al. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood 112, 5095–5102 (2008).
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).
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).
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).
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).
Migita, K. et al. Inhibitory effects of the JAK inhibitor CP690,550 on human CD4+ T lymphocyte cytokine production. BMC Immunol. 12, 51 (2011).
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).
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).
Derenzini, E. et al. The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. Blood Cancer J. 1, e46 (2011).
Hedvat, M. et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 16, 487–497 (2009).
McFarland, B. C. et al. Therapeutic potential of AZD1480 for the treatment of human glioblastoma. Mol. Cancer Ther. 10, 2384–2393 (2011).
Xin, H. et al. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res. 71, 6601–6610 (2011).
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).
Amit-Vazina, M. et al. Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells. Br. J. Cancer. 93, 70–80 (2005).
Kim, N. H. et al. Auranofin blocks interleukin-6 signaling by inhibiting phosphorylation of JAK1 and STAT3. Immunology 122, 607–614 (2007).
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).
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).
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).
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.
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).
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).
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).
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).
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).
Sen, M. et al. Targeting Stat3 abrogates EGFR inhibitor resistance in cancer. Clin. Cancer Res. 18, 4986–4996 (2012).
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).
Niu, G. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008 (2002).
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).
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).
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).
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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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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DOI: https://doi.org/10.1038/nrd4088
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