Inhibiting the Wnt Signaling Pathway with Small Molecules

  • Ho-Jin Lee
  • Xinxin Zhang
  • Jie J. ZhengEmail author


Wnt signaling plays important roles in embryonic development and in maintenance of adult tissues. Mutation, loss, or overexpression of key Wnt pathway components has been linked to various types of cancer. Therefore, inhibition of Wnt signaling is of interest for the development of novel anticancer agents. The results of recent structure-based screening, high-throughput screening (HTS), and chemical genomics studies demonstrate that small molecules, including synthetic and natural compounds, can inhibit Wnt signaling in various cancers by blocking specific protein–protein interactions or the activity of specific enzymes. In biological studies, these compounds appear promising as potential anticancer agents; however, their efficacy and toxicity have yet to be investigated. Small molecule inhibitors of Wnt signaling also have wide-ranging potential as tools for elucidating disease and basic biology. Indubitably, in the near future, these compounds will yield agents that are clinically useful against malignant diseases.


Ethacrynic Acid EGCG Treatment Quercetin Treatment SW480 Colon Cancer Cell Sulindac Sulfone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Adenomatous polyposis coli


Casein kinase 1


Chronic lymphocytic leukemia




Colon carcinoma


Dishevelled Egl-10, and pleckstrin


Dishevelled and axin




Ethacrynic acid




Glycogen synthase kinase-3


High-throughput screening


Low-density lipoprotein receptor (LDLR)-related protein


Multiple myeloma


Nuclear magnetic resonance


Nonsteroidal anti-inflammatory drugs


Nonsmall cell lung cancer


Peroxisome proliferator-activated receptor γ



We thank Sharon Naron for editorial help. This work is supported by the American Lebanese Syrian Associated Charities, by the Cancer Center Support Grant (CA21765) from the National Cancer Institute, and by National Institutes of Health Grant GM081492.


  1. Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398PubMedGoogle Scholar
  2. Arce L, Yokoyama NN, Waterman ML (2006) Diversity of LEF/TCF action in development and disease. Oncogene 25:7492–7504PubMedGoogle Scholar
  3. Barker N, Clevers H (2006) Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5:997–1014PubMedGoogle Scholar
  4. Bartscherer K, Boutros M (2008) Regulation of Wnt protein secretion and its role in gradient formation. EMBO Rep 9:977–982PubMedGoogle Scholar
  5. Batra S, Shi Y, Kuchenbecker KM, He B, Reguart N, Mikami I, You L, Xu Z, Lin YC, Clement G, Jablons DM (2006) Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hyper­methylation in malignant pleural mesothelioma. Biochem Biophys Res Commun 342:1228–1232PubMedGoogle Scholar
  6. Behari J, Zeng G, Otruba W, Thompson MD, Muller P, Micsenyi A, Sekhon SS, Leoni L, Monga SP (2007) R-Etodolac decreases beta-catenin levels along with survival and proliferation of hepatoma cells. J Hepatol 46:849–857PubMedGoogle Scholar
  7. Bengochea A, de Souza MM, Lefrancois L, Le RE, Galy O, Chemin I, Kim M, Wands JR, Trepo C, Hainaut P, Scoazec JY, Vitvitski L, Merle P (2008) Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer 99:143–150PubMedGoogle Scholar
  8. Bilic J, Huang YL, Davidson G, Zimmermann T, Cruciat CM, Bienz M, Niehrs C (2007) Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 316:1619–1622PubMedGoogle Scholar
  9. Boguski MS, Mandl KD, Sukhatme VP (2009) Drug discovery. Repurposing with a difference. Science 324:1394–1395PubMedGoogle Scholar
  10. Boon EM, Keller JJ, Wormhoudt TA, Giardiello FM, Offerhaus GJ, van der Neut R, Pals ST (2004) Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br J Cancer 90:224–229PubMedGoogle Scholar
  11. Bos CL, Kodach LL, van den Brink GR, Diks SH, van Santen MM, Richel DJ, Peppelenbosch MP, Hardwick JC (2006) Effect of aspirin on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A. Oncogene 25:6447–6456PubMedGoogle Scholar
  12. Cavallo R, Rubenstein D, Peifer M (1997) Armadillo and dTCF: a marriage made in the nucleus. Curr Opin Genet Dev 7:459–466PubMedGoogle Scholar
  13. Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K (2001) Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293:2080–2084PubMedGoogle Scholar
  14. Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L (2009a) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5:100–107PubMedGoogle Scholar
  15. Chen M, Wang J, Lu J, Bond MC, Ren XR, Lyerly HK, Barak LS, Chen W (2009b) The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry 48:10267–10274PubMedGoogle Scholar
  16. Chen Z, Venkatesan AM, Dehnhardt CM, Dos SO, Delos SE, yral-Kaloustian S, Chen L, Geng Y, Arndt KT, Lucas J, Chaudhary I, Mansour TS (2009c) 2, 4-Diamino-quinazolines as inhibitors of beta-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer. Bioorg Med Chem Lett 19:4980–4983PubMedGoogle Scholar
  17. Cheng AC, Coleman RG, Smyth KT, Cao Q, Soulard P, Caffrey DR, Salzberg AC, Huang ES (2007) Structure-based maximal affinity model predicts small-molecule druggability. Nat Biotechnol 25:71–75PubMedGoogle Scholar
  18. Cheyette BN, Waxman JS, Miller JR, Takemaru K, Sheldahl LC, Khlebtsova N, Fox EP, Earnest T, Moon RT (2002) Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK ­signaling, is required for notochord formation. Dev Cell 2:449–461PubMedGoogle Scholar
  19. Chiang YJ, Hsiao SJ, Yver D, Cushman SW, Tessarollo L, Smith S, Hodes RJ (2008) Tankyrase 1 and tankyrase 2 are essential but redundant for mouse embryonic development. PLoS ONE 3:e2639PubMedGoogle Scholar
  20. Choi H, Gwak J, Cho M, Ryu MJ, Lee JH, Kim SK, Kim YH, Lee GW, Yun MY, Cuong NM, Shin JG, Song GY, Oh S (2010) Murrayafoline A attenuates the Wnt/beta-catenin pathway by promoting the degradation of intracellular beta-catenin proteins. Biochem Biophys Res Commun 391:915–20PubMedGoogle Scholar
  21. Clement G, Guilleret I, He B, Yagui-Beltran A, Lin YC, You L, Xu Z, Shi Y, Okamoto J, Benhattar J, Jablons D (2008) Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett’s esophagus. Cancer Sci 99:46–53PubMedGoogle Scholar
  22. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480PubMedGoogle Scholar
  23. Clevers H, van de Wetering M (1997) TCF/LEF factor earn their wings. Trends Genet 13:485–489PubMedGoogle Scholar
  24. Corpet DE, Pierre F (2003) Point: from animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol Biomarkers Prev 12:391–400PubMedGoogle Scholar
  25. Dashwood WM, Orner GA, Dashwood RH (2002) Inhibition of beta-catenin/Tcf activity by white tea, green tea, and epigallocatechin-3-gallate (EGCG): minor contribution of H(2)O(2) at physiologically relevant EGCG concentrations. Biochem Biophys Res Commun 296:584–588PubMedGoogle Scholar
  26. Demerson CA, Humber LG, Abraham NA, Schilling G, Martel RR, Pace-Asciak C (1983) Resolution of etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers. J Med Chem 26:1778–1780PubMedGoogle Scholar
  27. Deschner EE, Ruperto JF, Wong GY, Newmark HL (1993) The effect of dietary quercetin and rutin on AOM-induced acute colonic epithelial abnormalities in mice fed a high-fat diet. Nutr Cancer 20:199–204PubMedGoogle Scholar
  28. Dihlmann S, von Knebel DM (2005) Wnt/beta-catenin-pathway as a molecular target for future anti-cancer therapeutics. Int J Cancer 113:515–524PubMedGoogle Scholar
  29. Doghman M, Cazareth J, Lalli E (2008) The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells. J Clin Endocrinol Metab 93:3222–3225PubMedGoogle Scholar
  30. Dorfman DM, Greisman HA, Shahsafaei A (2003) Loss of expression of the WNT/beta-catenin-signaling pathway transcription factors lymphoid enhancer factor-1 (LEF-1) and T cell factor-1 (TCF-1) in a subset of peripheral T cell lymphomas. Am J Pathol 162:1539–1544PubMedGoogle Scholar
  31. Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, Henry E, Dicato M, Diederich M (2005) Chemopreventive and therapeutic effects of curcumin. Cancer Lett 223:181–190PubMedGoogle Scholar
  32. Edelson S (2009) Clearing the path to Wnt. SciBX 2(37):1Google Scholar
  33. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo JL, Kim HY, Moon SH, Ha JR, Kahn M (2004) A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA 101:12682–12687PubMedGoogle Scholar
  34. Esaki M, Matsumoto T, Mizuno M, Kobori Y, Yoshimura R, Yao T, Iida M (2002) Effect of sulindac treatment for attenuated familial adenomatous polyposis with a new germline APC mutation at codon 161: report of a case. Dis Colon Rectum 45:1397–1402PubMedGoogle Scholar
  35. Ewan KB, Dale TC (2008) The potential for targeting oncogenic WNT/beta-catenin signaling in therapy. Curr Drug Targets 9:532–547PubMedGoogle Scholar
  36. Fearon ER (2009) PARsing the phrase “all in for Axin”- Wnt pathway targets in cancer. Cancer Cell 16:366–368PubMedGoogle Scholar
  37. Feng R, Lentzsch S (2007) Treatment of multiple myeloma with SDX-308. Drug News Perspect 20:431–435PubMedGoogle Scholar
  38. Feng R, Anderson G, Xiao G, Elliott G, Leoni L, Mapara MY, Roodman GD, Lentzsch S (2007) SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-kappaB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth. Blood 109:2130–2138PubMedGoogle Scholar
  39. Fournier DB, Gordon GB (2000) COX-2 and colon cancer: potential targets for chemoprevention. J Cell Biochem Suppl 34:97–102PubMedGoogle Scholar
  40. Fujii N, You L, Xu Z, Uematsu K, Shan J, He B, Mikami I, Edmondson LR, Neale G, Zheng J, Guy RK, Jablons DM (2007) An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Res 67:573–579PubMedGoogle Scholar
  41. Gao J, Liu X, Rigas B (2005) Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress. Proc Natl Acad Sci USA 102:17207–17212PubMedGoogle Scholar
  42. Gao Z, Xu Z, Hung MS, Lin YC, Wang T, Gong M, Zhi X, Jablon DM, You L (2009) Promoter demethylation of WIF-1 by epigallocatechin-3-gallate in lung cancer cells. Anticancer Res 29:2025–2030PubMedGoogle Scholar
  43. Glavin GB, Sitar DS (1986) The effects of sulindac and its metabolites on acute stress-induced gastric ulcers in rats. Toxicol Appl Pharmacol 83:386–389PubMedGoogle Scholar
  44. Goluboff ET, Shabsigh A, Saidi JA, Weinstein IB, Mitra N, Heitjan D, Piazza GA, Pamukcu R, Buttyan R, Olsson CA (1999) Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis. Urology 53:440–445PubMedGoogle Scholar
  45. Graham TA, Weaver C, Mao F, Kimelman D, Xu W (2000) Crystal structure of a beta-catenin/Tcf complex. Cell 103:885–896PubMedGoogle Scholar
  46. Graham TA, Ferkey DM, Mao F, Kimelman D, Xu W (2001) Tcf4 can specifically recognize beta-catenin using alternative conformations. Nat Struct Biol 8:1048–1052PubMedGoogle Scholar
  47. Graham TA, Clements WK, Kimelman D, Xu W (2002) The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. Mol Cell 10:563–571PubMedGoogle Scholar
  48. Grandy D, Shan J, Zhang X, Rao S, Akunuru S, Li H, Zhang Y, Alpatov I, Zhang XA, Lang RA, Shi DL, Zheng JJ (2009) Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J Biol Chem 284:16256–16263PubMedGoogle Scholar
  49. Gwak J, Song T, Song JY, Yun YS, Choi IW, Jeong Y, Shin JG, Oh S (2009) Isoreserpine promotes beta-catenin degradation via Siah-1 up-regulation in HCT116 colon cancer cells. Biochem Biophys Res Commun 387:444–449PubMedGoogle Scholar
  50. Hale KJ, Manaviazar S, Lazarides L, George J, Walters MA, Cai J, Delisser VM, Bhatia GS, Peak SA, Dalby SM, Lefranc A, Chen YN, Wood AW, Crowe P, Erwin P, El-Tanani M (2009) Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb. Org Lett 11:737–740PubMedGoogle Scholar
  51. Han EK, Arber N, Yamamoto H, Lim JT, Delohery T, Pamukcu R, Piazza GA, Xing WQ, Weinstein IB (1998) Effects of sulindac and its metabolites on growth and apoptosis in human mammary epithelial and breast carcinoma cell lines. Breast Cancer Res Treat 48:195–203PubMedGoogle Scholar
  52. Han A, Song Z, Tong C, Hu D, Bi X, Augenlicht LH, Yang W (2008) Sulindac suppresses beta-catenin expression in human cancer cells. Eur J Pharmacol 583:26–31PubMedGoogle Scholar
  53. Herbst A, Kolligs FT (2007) Wnt signaling as a therapeutic target for cancer. Methods Mol Biol 361:63–91PubMedGoogle Scholar
  54. Hope C, Planutis K, Planutiene M, Moyer MP, Johal KS, Woo J, Santoso C, Hanson JA, Holcombe RF (2008) Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: implications for colon cancer prevention. Mol Nutr Food Res 52(suppl 1):S52–S61PubMedGoogle Scholar
  55. Hsiao SJ, Smith S (2008) Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 90:83–92PubMedGoogle Scholar
  56. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620PubMedGoogle Scholar
  57. Huber AH, Weis WI (2001) The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. Cell 105:391–402PubMedGoogle Scholar
  58. Huber AH, Nelson WJ, Weis WI (1997) Three-dimensional structure of the armadillo repeat region of beta-catenin. Cell 90:871–882PubMedGoogle Scholar
  59. James RG, Biechele TL, Conrad WH, Camp ND, Fass DM, Major MB, Sommer K, Yi X, Roberts BS, Cleary MA, Arthur WT, MacCoss M, Rawlings DJ, Haggarty SJ, Moon RT (2009) Bruton’s tyrosine kinase revealed as a negative regulator of Wnt-beta-catenin signaling. Sci Signal 2:ra25PubMedGoogle Scholar
  60. Jin G, Lu D, Yao S, Wu CC, Liu JX, Carson DA, Cottam HB (2009) Amide derivatives of ethacrynic acid: synthesis and evaluation as antagonists of Wnt/beta-catenin signaling and CLL cell survival. Bioorg Med Chem Lett 19:606–609PubMedGoogle Scholar
  61. Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci USA 93:13–20PubMedGoogle Scholar
  62. Kawamoto SA, Thompson AD, Coleska A, Nikolovska-Coleska Z, Yi H, Wang S (2009) Analysis of the interaction of BCL9 with beta-catenin and development of fluorescence polarization and surface plasmon resonance binding assays for this interaction. Biochemistry 48:9534–9541PubMedGoogle Scholar
  63. Keller JJ, Giardiello FM (2003) Chemoprevention strategies using NSAIDs and COX-2 inhibitors. Cancer Biol Ther 2:S140–S149PubMedGoogle Scholar
  64. Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubet RA, Doody LA, Malone WF, Hawk ET, Sigman CC (1996) New agents for cancer chemoprevention. J Cell Biochem Suppl 26:1–28PubMedGoogle Scholar
  65. Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, Yee AS (2006) Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem 281:10865–10875PubMedGoogle Scholar
  66. Koehne CH, DuBois RN (2004) COX-2 inhibition and colorectal cancer. Semin Oncol 31:12–21PubMedGoogle Scholar
  67. Koornstra JJ, Rijcken FE, Oldenhuis CN, Zwart N, van der Sluis T, Hollema H, deVries EG, Keller JJ, Offerhaus JA, Giardiello FM, Kleibeuker JH (2005) Sulindac inhibits beta-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients. Cancer Epidemiol Biomarkers Prev 14:1608–1612PubMedGoogle Scholar
  68. Kuo SM (1996) Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett 110:41–48PubMedGoogle Scholar
  69. Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P (1991) Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101:635–639PubMedGoogle Scholar
  70. Lee HJ, Wang NX, Shi DL, Zheng JJ (2009a) Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of the protein Dishevelled. Angew Chem Int Ed Engl 48:6448–6452PubMedGoogle Scholar
  71. Lee H-J, Wang NX, Shao Y, Zheng JJ (2009b) Identification of tripeptides recognized by the PDZ domain of Dishevelled. Bioorg Med Chem 17:1701–1708PubMedGoogle Scholar
  72. Lentzsch S, Elliott G, Roodman GD (2007) SDX-308 and SDX-101, non-steroidal anti-­inflammatory drugs, as therapeutic candidates for treating hematologic malignancies including myeloma. Arch Pharm (Weinheim) 340:511–516Google Scholar
  73. Leow PC, Ong ZY, Ee PL (2010a) Natural compounds as antagonists of canonical Wnt/β-catenin signaling. Curr Chem Biol 4:49–63Google Scholar
  74. Leow PC, Tian Q, Ong ZY, Yang Z, Ee PL (2010b) Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/beta-catenin antagonists against human osteosarcoma cells. Invest New Drugs 28:766–782PubMedGoogle Scholar
  75. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F, Bruseo C, Wood AW, Shivdasani RA (2004) Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 5:91–102PubMedGoogle Scholar
  76. Li X, Ohtsuki T, Koyano T, Kowithayakorn T, Ishibashi M (2009) New Wnt/beta-catenin signaling inhibitors isolated from Eleutherine palmifolia. Chem Asian J 4:540–547PubMedGoogle Scholar
  77. Lim JT, Joe AK, Suzui M, Shimizu M, Masuda M, Weinstein IB (2006) Sulindac sulfide and exisulind inhibit expression of the estrogen and progesterone receptors in human breast cancer cells. Clin Cancer Res 12:3478–3484PubMedGoogle Scholar
  78. Lin YC, You L, Xu Z, He B, Mikami I, Thung E, Chou J, Kuchenbecker K, Kim J, Raz D, Yang CT, Chen JK, Jablons DM (2006) Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines. Biochem Biophys Res Commun 341:635–640PubMedGoogle Scholar
  79. Lindhagen E, Nissle S, Leoni L, Elliott G, Chao Q, Larsson R, Aleskog A (2007a) R-etodolac (SDX-101) and the related indole-pyran analogues SDX-308 and SDX-309 potentiate the antileukemic activity of standard cytotoxic agents in primary chronic lymphocytic leukaemia cells. Cancer Chemother Pharmacol 60:545–553PubMedGoogle Scholar
  80. Lindhagen E, Rickardson L, Elliott G, Leoni L, Nygren P, Larsson R, Aleskog A (2007b) Pharmacological profiling of novel non-COX-inhibiting indole-pyran analogues of etodolac reveals high solid tumour activity of SDX-308 in vitro. Invest New Drugs 25:297–303PubMedGoogle Scholar
  81. Liu JJ, Wang JY, Hertervig E, Nilsson A, Duan RD (2002) Sulindac induces apoptosis, inhibits proliferation and activates caspase-3 in Hep G2 cells. Anticancer Res 22:263–266PubMedGoogle Scholar
  82. Liu J, Xing Y, Hinds TR, Zheng J, Xu W (2006) The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin. J Mol Biol 360:133–144PubMedGoogle Scholar
  83. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810PubMedGoogle Scholar
  84. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, Kipps TJ, Corr M, Carson DA (2004) Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 101:3118–3123PubMedGoogle Scholar
  85. Lu D, Cottam HB, Corr M, Carson DA (2005) Repression of beta-catenin function in malignant cells by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci USA 102:18567–18571PubMedGoogle Scholar
  86. Lu D, Liu JX, Endo T, Zhou H, Yao S, Willert K, Schmidt-Wolf IG, Kipps TJ, Carson DA (2009a) Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway. PLoS One 4:e8294PubMedGoogle Scholar
  87. Lu J, Ma Z, Hsieh JC, Fan CW, Chen B, Longgood JC, Williams NS, Amatruda JF, Lum L, Chen C (2009b) Structure-activity relationship studies of small-molecule inhibitors of Wnt response. Bioorg Med Chem Lett 19:3825–3827PubMedGoogle Scholar
  88. Lu W, Tinsley HN, Keeton A, Qu Z, Piazza GA, Li Y (2009c) Suppression of Wnt/beta-catenin signaling inhibits prostate cancer cell proliferation. Eur J Pharmacol 602:8–14PubMedGoogle Scholar
  89. Ma H, Nguyen C, Lee KS, Kahn M (2005) Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene 24:3619–3631PubMedGoogle Scholar
  90. Mahmoudi T, Li VS, Ng SS, Taouatas N, Vries RG, Mohammed S, Heck AJ, Clevers H (2009) The kinase TNIK is an essential activator of Wnt target genes. EMBO J 28:3329–3340PubMedGoogle Scholar
  91. Matsumoto T, Nakamura S, Esaki M, Yao T, Iida M (2006) Effect of the non-steroidal anti-inflammatory drug sulindac on colorectal adenomas of uncolectomized familial adenomatous polyposis. J Gastroenterol Hepatol 21:251–257PubMedGoogle Scholar
  92. Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, Reguart N, Rosell R, McCormick F, Jablons DM (2004) Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. Cancer Res 64:4717–4720PubMedGoogle Scholar
  93. McMillan M, Kahn M (2005) Investigating Wnt signaling: a chemogenomic safari. Drug Discov Today 10:1467–1474PubMedGoogle Scholar
  94. Minke KS, Staib P, Puetter A, Gehrke I, Gandhirajan RK, Schlosser A, Schmitt EK, Hallek M, Kreuzer KA (2009) Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells. Eur J Haematol 82:165–175PubMedGoogle Scholar
  95. Mizutani K, Miyamoto S, Nagahata T, Konishi N, Emi M, Onda M (2005) Upregulation and overexpression of DVL1, the human counterpart of the Drosophila dishevelled gene, in prostate cancer. Tumori 91:546–551PubMedGoogle Scholar
  96. Moon RT, Kohn AD, De Ferrari GV, Kaykas A (2004) WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5:691–701PubMedGoogle Scholar
  97. Nagahata T, Shimada T, Harada A, Nagai H, Onda M, Yokoyama S, Shiba T, Jin E, Kawanami O, Emi M (2003) Amplification, up-regulation and over-expression of DVL-1, the human counterpart of the Drosophila disheveled gene, in primary breast cancers. Cancer Sci 94:515–518PubMedGoogle Scholar
  98. Nath N, Kashfi K, Chen J, Rigas B (2003) Nitric oxide-donating aspirin inhibits beta-catenin/T cell factor (TCF) signaling in SW480 colon cancer cells by disrupting the nuclear beta-catenin-TCF association. Proc Natl Acad Sci USA 100:12584–12589PubMedGoogle Scholar
  99. Nath N, Vassell R, Chattopadhyay M, Kogan M, Kashfi K (2009) Nitro-aspirin inhibits MCF-7 breast cancer cell growth: effects on COX-2 expression and Wnt/beta-catenin/TCF-4 signaling. Biochem Pharmacol 78:1298–1304PubMedGoogle Scholar
  100. Nguyen DX, Chiang AC, Zhang XH, Kim JY, Kris MG, Ladanyi M, Gerald WL, Massague J (2009) WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138:51–62PubMedGoogle Scholar
  101. Nikitakis NG, Hebert C, Lopes MA, Reynolds MA, Sauk JJ (2002) PPARgamma-mediated antineoplastic effect of NSAID sulindac on human oral squamous carcinoma cells. Int J Cancer 98:817–823PubMedGoogle Scholar
  102. Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK (1993) Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 80:1618–1619PubMedGoogle Scholar
  103. Okino K, Nagai H, Hatta M, Nagahata T, Yoneyama K, Ohta Y, Jin E, Kawanami O, Araki T, Emi M (2003) Up-regulation and overproduction of DVL-1, the human counterpart of the Drosophila dishevelled gene, in cervical squamous cell carcinoma. Oncol Rep 10:1219–1223PubMedGoogle Scholar
  104. Park CH, Chang JY, Hahm ER, Park S, Kim HK, Yang CH (2005) Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commu 328:227–234Google Scholar
  105. Park S, Gwak J, Cho M, Song T, Won J, Kim DE, Shin JG, Oh S (2006) Hexachlorophene inhibits Wnt/beta-catenin pathway by promoting Siah-mediated beta-catenin degradation. Mol Pharmacol 70:960–966PubMedGoogle Scholar
  106. Pasricha PJ, Bedi A, O’Connor K, Rashid A, Akhtar AJ, Zahurak ML, Piantadosi S, Hamilton SR, Giardiello FM (1995) The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis. Gastroenterology 109:994–998PubMedGoogle Scholar
  107. Patten EJ, DeLong MJ (1999) Effects of sulindac, sulindac metabolites, and aspirin on the activity of detoxification enzymes in HT-29 human colon adenocarcinoma cells. Cancer Lett 147:95–100PubMedGoogle Scholar
  108. Peterson RT (2009) Drug discovery: propping up a destructive regime. Nature 461:599–600PubMedGoogle Scholar
  109. Petropoulos K, Arseni N, Schessl C, Stadler CR, Rawat VP, Deshpande AJ, Heilmeier B, Hiddemann W, Quintanilla-Martinez L, Bohlander SK, Feuring-Buske M, Buske C (2008) A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med 205:515–522PubMedGoogle Scholar
  110. Piazza GA, Alberts DS, Hixson LJ, Paranka NS, Li H, Finn T, Bogert C, Guillen JM, Brendel K, Gross PH, Sperl G, Ritchie J, Burt RW, Ellsworth L, Ahnen DJ, Pamukcu R (1997) Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res 57:2909–2915PubMedGoogle Scholar
  111. Piergentill A, Bello FD, Gentili F, Giannella M, Quaglia W, Vesprini C, Thomas RJ, Robertson GM (2007) Solution-phase synthesis of ICG-001, a β-turn peptidomimetic molecule inhibitor of β-catenin–Tcf-mediated transcription. Tetrahedron 63:12912–12916Google Scholar
  112. Poy F, Lepourcelet M, Shivdasani RA, Eck MJ (2001) Structure of a human Tcf4-beta-catenin complex. Nat Struct Biol 8:1053–1057PubMedGoogle Scholar
  113. Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R (2009) Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem Biol Interact 181(2):263–271Google Scholar
  114. Rahman MA, Dhar DK, Masunaga R, Yamanoi A, Kohno H, Nagasue N (2000) Sulindac and exisulind exhibit a significant antiproliferative effect and induce apoptosis in human hepatocellular carcinoma cell lines. Cancer Res 60:2085–2089PubMedGoogle Scholar
  115. Ravindranath A, O’Connell A, Johnston PG, El-Tanani MK (2008) The role of LEF/TCF factors in neoplastic transformation. Curr Mol Med 8:38–50PubMedGoogle Scholar
  116. Reguart N, He B, Xu Z, You L, Lee AY, Mazieres J, Mikami I, Batra S, Rosell R, McCormick F, Jablons DM (2004) Cloning and characterization of the promoter of human Wnt inhibitory factor-1. Biochem Biophys Res Commun 323:229–234PubMedGoogle Scholar
  117. Rigas B (2007) Novel agents for cancer prevention based on nitric oxide. Biochem Soc Trans 35:1364–1368PubMedGoogle Scholar
  118. Rigas B, Kashfi K (2004) Nitric-oxide-donating NSAIDs as agents for cancer prevention. Trends Mol Med 10:324–330PubMedGoogle Scholar
  119. Rigas B, Williams JL (2008) NO-donating NSAIDs and cancer: an overview with a note on whether NO is required for their action. Nitric Oxide 19:199–204PubMedGoogle Scholar
  120. Roccaro AM, Leleu X, Sacco A, Moreau AS, Hatjiharissi E, Jia X, Xu L, Ciccarelli B, Patterson CJ, Ngo HT, Russo D, Vacca A, Dammacco F, Anderson KC, Ghobrial IM, Treon SP (2008) Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenstrom’s macroglobulinemia. Clin Cancer Res 14:1849–1858PubMedGoogle Scholar
  121. Roose J, Clevers H (1999) TCF transcription factors: molecular switches in carcinogenesis. Biochim Biophys Acta 1424:M23–M37PubMedGoogle Scholar
  122. Ryu MJ, Cho M, Song JY, Yun YS, Choi IW, Kim DE, Park BS, Oh S (2008) Natural derivatives of curcumin attenuate the Wnt/beta-catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem Biophys Res Commun 377:1304–1308PubMedGoogle Scholar
  123. Sakoguchi-Okada N, Takahashi-Yanaga F, Fukada K, Shiraishi F, Taba Y, Miwa Y, Morimoto S, Iida M, Sasaguri T (2007) Celecoxib inhibits the expression of survivin via the suppression of promoter activity in human colon cancer cells. Biochem Pharmacol 73:1318–1329PubMedGoogle Scholar
  124. Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W (2006) Crystal structure of a beta-catenin/BCL9/Tcf4 complex. Mol Cell 24:293–300PubMedGoogle Scholar
  125. Sarkar FH, Li Y, Wang Z, Kong D (2009) Cellular signaling perturbation by natural products. Cell Signal 21:1541–1547PubMedGoogle Scholar
  126. Schwarz-Romond T, Fiedler M, Shibata N, Butler PJ, Kikuchi A, Higuchi Y, Bienz M (2007) The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nat Struct Mol Biol 14:484–492PubMedGoogle Scholar
  127. Shan J, Shi DL, Wang J, Zheng J (2005) Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 44:15495–15503PubMedGoogle Scholar
  128. Shan BE, Wang MX, Li RQ (2009) Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Invest 27:604–612Google Scholar
  129. Shan J, Zheng JJ (2009) J Comput Aided Mol Des 23:37–47PubMedGoogle Scholar
  130. Sharma M, Li L, Celver J, Killian C, Kovoor A, Seeram NP (2009) Effects of fruit ellagitannin extracts, ellagic acid, and their colonic metabolite, urolithin A, on Wnt signaling (dagger). J Agric Food Chem 58:3965–3969Google Scholar
  131. Simons M, Gault WJ, Gotthardt D, Rohatgi R, Klein TJ, Shao Y, Lee HJ, Wu AL, Fang Y, Satlin LM, Dow JT, Chen J, Zheng J, Boutros M, Mlodzik M (2009) Electrochemical cues regulate ­assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization. Nat Cell Biol 11:286–294PubMedGoogle Scholar
  132. Song GY, Lee JH, Cho M, Park BS, Kim DE, Oh S (2007) Decursin suppresses human androgen-independent PC3 prostate cancer cell proliferation by promoting the degradation of beta-catenin. Mol Pharmacol 72:1599–1606PubMedGoogle Scholar
  133. Suh Y, Afaq F, Johnson JJ, Mukhtar H (2009) A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis 30:300–307PubMedGoogle Scholar
  134. Sukhdeo K, Mani M, Zhang Y, Dutta J, Yausi H, Rooney MD, Carrasco DE, Zheng M, He H, Tai YT, Mitsiades C, Anderson KC, Carrasco DR (2007) Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci USA 104:7516–7521Google Scholar
  135. Takada R, Satomi Y, Kurata T, Ueno N, Norioka S, Kondoh H, Takao T, Takada S (2006) Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell 11:791–801PubMedGoogle Scholar
  136. Takahashi-Yanaga F, Sasaguri T (2007) The Wnt/beta-catenin signaling pathway as a target in drug discovery. J Pharmacol Sci 104:293–302PubMedGoogle Scholar
  137. Takahashi-Yanaga F, Yoshihara T, Jingushi K, Miwa Y, Morimoto S, Hirata M, Sasaguri T (2008) Celecoxib-induced degradation of T-cell factors-1 and -4 in human colon cancer cells. Biochem Biophys Res Commun 377:1185–1190PubMedGoogle Scholar
  138. Takemaru KI, Moon RT (2000) The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J Cell Biol 149:249–254PubMedGoogle Scholar
  139. Takemaru KI, Ohmitsu M, Li FQ (2008) An oncogenic hub: beta-catenin as a molecular target for cancer therapeutics. Handb Exp Pharmacol (186):261–284Google Scholar
  140. Teiten MH, Eifes S, Dicato M, Diederich M (2010) Curcumin-the paradigm of a multi-target natural compound with application in cancer prevention and treatment. Toxins 2:128–162Google Scholar
  141. Thun MJ, Henley SJ, Patrono C (2002) Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 94:252–266PubMedGoogle Scholar
  142. Toney JH, Fasick JI, Singh S, Beyrer C, Sullivan DJ Jr (2009) Purposeful learning with drug repurposing. Science 325:1339–1340PubMedGoogle Scholar
  143. Trosset JY, Dalvit C, Knapp S, Fasolini M, Veronesi M, Mantegani S, Gianellini LM, Catana C, Sundstrom M, Stouten PF, Moll JK (2006) Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening. Proteins 64:60–67PubMedGoogle Scholar
  144. Uematsu K, He B, You L, Xu Z, McCormick F, Jablons DM (2003a) Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene 22:7218–7221PubMedGoogle Scholar
  145. Uematsu K, Kanazawa S, You L, He B, Xu Z, Li K, Peterlin BM, McCormick F, Jablons DM (2003b) Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of beta-catenin. Cancer Res 63:4547–4551PubMedGoogle Scholar
  146. Waddell WR (1994) The effect of sulindac on colon polyps: circumvention of a transformed phenotype–a hypothesis. J Surg Oncol 55:52–55PubMedGoogle Scholar
  147. Wallingford JB, Habas R (2005) The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 132:4421–4436PubMedGoogle Scholar
  148. Wang NX, Lee HJ, Zheng JJ (2008) Therapeutic use of PDZ protein-protein interaction antagonism. Drug News Perspect 21:137–141PubMedGoogle Scholar
  149. Webster WS, Leibovich BC (2005) Exisulind in the treatment of prostate cancer. Expert Rev Anticancer Ther 5:957–962PubMedGoogle Scholar
  150. Wei Q, Zhao Y, Yang ZQ, Dong QZ, Dong XJ, Han Y, Zhao C, Wang EH (2008) Dishevelled family proteins are expressed in non-small cell lung cancer and function differentially on tumor progression. Lung Cancer 62:181–192PubMedGoogle Scholar
  151. Wei W, Chua MS, Grepper S, So S (2010) Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int J Cancer 126:2426–2436Google Scholar
  152. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009PubMedGoogle Scholar
  153. Wharton KA Jr (2003) Runnin’ with the Dvl: proteins that associate with Dsh/Dvl and their significance to Wnt signal transduction. Dev Biol 253:1–17PubMedGoogle Scholar
  154. Whitehead CM, Earle KA, Fetter J, Xu S, Hartman T, Chan DC, Zhao TL, Piazza G, Klein-Szanto AJ, Pamukcu R, Alila H, Bunn PA Jr, Thompson WJ (2003) Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival. Mol Cancer Ther 2:479–488PubMedGoogle Scholar
  155. Winde G, Gumbinger HG, Osswald H, Kemper F, Bunte H (1993) The NSAID sulindac reverses rectal adenomas in colectomized patients with familial adenomatous polyposis: clinical results of a dose-finding study on rectal sulindac administration. Int J Colorectal Dis 8:13–17PubMedGoogle Scholar
  156. Wong HC, Mao J, Nguyen JT, Srinivas S, Zhang W, Liu B, Li L, Wu D, Zheng J (2000) Structural basis of the recognition of the dishevelled DEP domain in the Wnt signaling pathway. Nat Struct Biol 7:1178–1184PubMedGoogle Scholar
  157. Wong HC, Bourdelas A, Krauss A, Lee HJ, Shao Y, Wu D, Mlodzik M, Shi DL, Zheng J (2003) Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell 12:1251–1260PubMedGoogle Scholar
  158. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132:387–396PubMedGoogle Scholar
  159. Yang TM, Leu SW, Li JM, Hung MS, Lin CH, Lin YC, Huang TJ, Tsai YH, Yang CT (2009) WIF-1 promoter region hypermethylation as an adjuvant diagnostic marker for non-small cell lung cancer-related malignant pleural effusions. J Cancer Res Clin Oncol 135:919–924PubMedGoogle Scholar
  160. Yasui H, Hideshima T, Hamasaki M, Roccaro AM, Shiraishi N, Kumar S, Tassone P, Ishitsuka K, Raje N, Tai YT, Podar K, Chauhan D, Leoni LM, Kanekal S, Elliott G, Munshi NC, Anderson KC (2005) SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. Blood 106:706–712PubMedGoogle Scholar
  161. Yasui H, Hideshima T, Ikeda H, Ocio EM, Kiziltepe T, Vallet S, Okawa Y, Neri P, Sukhdeo K, Podar K, Chauhan D, Richardson PG, Raje N, Carrasco DR, Anderson KC (2007) Novel etodolac analog SDX-308 (CEP-18082) induces cytotoxicity in multiple myeloma cells associated with inhibition of beta-catenin/TCF pathway. Leukemia 21:535–540PubMedGoogle Scholar
  162. Yeh RK, Chen J, Williams JL, Baluch M, Hundley TR, Rosenbaum RE, Kalala S, Traganos F, Benardini F, Del SP, Kashfi K, Rigas B (2004) NO-donating nonsteroidal antiinflammatory drugs (NSAIDs) inhibit colon cancer cell growth more potently than traditional NSAIDs: a general pharmacological property? Biochem Pharmacol 67:2197–2205PubMedGoogle Scholar
  163. You L, Xu Z, Punchihewa C, Jablons DM, Fujii N (2008) Evaluation of a chemical library of small-molecule Dishevelled antagonists that suppress tumor growth by down-regulating T-cell factor-mediated transcription. Mol Cancer Ther 7:1633–1638PubMedGoogle Scholar
  164. Zeng X, Huang H, Tamai K, Zhang XJ, Harada Y, Yokota C, Almeida K, Wang J, Doble B, Woodgett J, Wynshaw-Boris A, Hsieh JC, He X (2008) Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135:367–375PubMedGoogle Scholar
  165. Zhang T, Fields JZ, Ehrlich SM, Boman BM (2004) The chemopreventive agent sulindac attenuates expression of the antiapoptotic protein survivin in colorectal carcinoma cells. J Pharmacol Exp Ther 308:434–437PubMedGoogle Scholar
  166. Zhang Y, Appleton BA, Wiesmann C, Lau T, Costa M, Hannoush RN, Sidhu SS (2009) Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nat Chem Biol 5:217–219PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Structural BiologySt. Jude Children’s Research HospitalMemphisUSA

Personalised recommendations