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Investigational New Drugs

, Volume 30, Issue 5, pp 1878–1886 | Cite as

Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors

  • Yoshihiko Fujita
  • Rafiqul Islam
  • Kazuko Sakai
  • Hiroyasu Kaneda
  • Kanae Kudo
  • Daisuke Tamura
  • Keiichi Aomatsu
  • Tomoyuki Nagai
  • Hidekazu Kimura
  • Kazuko Matsumoto
  • Marco A. de Velasco
  • Tokuzo Arao
  • Tadashi Okawara
  • Kazuto NishioEmail author
PRECLINICAL STUDIES

Summary

Resveratrol (3, 4′, 5-trihydroxy-trans-stilbene), a natural phytoalexin found in grapes and wine, has anti-proliferative activity on human-derived cancer cells. In our study, we used a conventional condensation reaction between aldehydes and amines to provide a number of aza-resveratrol (3, 4′, 5-trihydroxy-trans- aza-stilbene) derivatives in an attempt to screen for compounds with resveratrol’s action but with increased potency. Aza-resveratrol and its hydroxylated derivative (3, 4, 4′, 5-tetrahydroxy-trans- aza-stilbene) showed a more enhanced anti-proliferative effect than resveratrol in an MCF-7 breast carcinoma cell line. To identify the cellular targets of the aza derivatives of resveratrol, we conjugated the latter aza-stilbene compound with epoxy-activated agarose and performed affinity purification. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, was identified as a major target protein in MCF-7 cell lysates using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS). The aza-resveratrol and its hydroxylated derivative, but not resveratrol, were also found to be potent inhibitors of MIF tautomerase activity, which may be associated with their inhibitory effects on MIF bioactivity for cell growth.

Keywords

Resveratrol Cancer Macrophage migration inhibitory factor (MIF) Tautomerase, CD74 

Notes

Acknowledgements

We thank Eiko Honda for performing the MALDI-TOF MASS spectrometry, Yoshitaka Horiuchi for the microscopic analysis and Tomoko Kitayama for cell experiments.

Disclosure of potential conflicts of interest

No potential conflicts of interests were disclosed.

Funding

This work was supported by funds for the Comprehensive 3rd term of the 10-Year Strategy for Cancer Control, a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19209018).

Supplementary material

10637_2011_9749_MOESM1_ESM.pdf (40 kb)
Supplementary Fig. 1 Immunoblot analysis of endogenous expression levels of MIF for several cell lines. Subconfluent cells were lysed with buffer containing 0.5% NP-40, 150 mM NaCl, 50 mM Tris–HCl (pH 7.4), 10 mM sodium pyrophosphate and protease inhibitor mix, completeTM (Roche Diagnostics). Thirty μg of protein from each cell line was used for SDS-polyacrylamide gel electrophoresis and transferred onto PVDF membrane, which were then treated with anti-MIF and anti-β-actin antibodies. After incubation with horseradish peroxidase-conjugated secondary antibody, the membrane was visualized using ECL detection system (GE Healthcare Life Science) (PPT 11470 kb)

References

  1. 1.
    Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R (1995) MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377:68–71PubMedCrossRefGoogle Scholar
  2. 2.
    Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R (1993) MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365:756–759PubMedCrossRefGoogle Scholar
  3. 3.
    Meyer-Siegler KL, Iczkowski KA, Leng L, Bucala R, Vera PL (2006) Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. J Immunol 177:8730–8739PubMedGoogle Scholar
  4. 4.
    Hagemann T, Robinson SC, Thompson RG, Charles K, Kulbe H, Balkwill FR (2007) Ovarian cancer cell-derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis. Mol Cancer Ther 6:1993–2002PubMedCrossRefGoogle Scholar
  5. 5.
    Meyer-Siegler K (2000) Increased stability of macrophage migration inhibitory factor (MIF) in DU-145 prostate cancer cells. J Interferon Cytokine Res 20:769–778PubMedCrossRefGoogle Scholar
  6. 6.
    del Vecchio MT, Tripodi SA, Arcuri F, Pergola L, Hako L, Vatti R, Cintorino M (2000) Macrophage migration inhibitory factor in prostatic adenocarcinoma: correlation with tumor grading and combination endocrine treatment-related changes. Prostate 45:51–57PubMedCrossRefGoogle Scholar
  7. 7.
    Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH (1999) A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 190:1375–1382PubMedCrossRefGoogle Scholar
  8. 8.
    Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss R, Moll U, Muller W, Bucala R (2003) The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci USA 100:9354–9359PubMedCrossRefGoogle Scholar
  9. 9.
    Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J, Bucala R (2002) Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl Acad Sci USA 99:345–350PubMedCrossRefGoogle Scholar
  10. 10.
    Nguyen MT, Lue H, Kleemann R, Thiele M, Tolle G, Finkelmeier D, Wagner E, Braun A, Bernhagen J (2003) The cytokine macrophage migration inhibitory factor reduces pro-oxidative stress-induced apoptosis. J Immunol 170:3337–3347PubMedGoogle Scholar
  11. 11.
    Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R (2003) MIF signal transduction initiated by binding to CD74. J Exp Med 197:1467–1476PubMedCrossRefGoogle Scholar
  12. 12.
    Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R (2006) CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 25:595–606PubMedCrossRefGoogle Scholar
  13. 13.
    Nguyen MT, Beck J, Lue H, Funfzig H, Kleemann R, Koolwijk P, Kapurniotu A, Bernhagen J (2003) A 16-residue peptide fragment of macrophage migration inhibitory factor, MIF-(50–65), exhibits redox activity and has MIF-like biological functions. J Biol Chem 278:33654–33671PubMedCrossRefGoogle Scholar
  14. 14.
    Jung H, Seong HA, Ha H (2008) Critical role of cysteine residue 81 of macrophage migration inhibitory factor (MIF) in MIF-induced inhibition of p53 activity. J Biol Chem 283:20383–20396PubMedCrossRefGoogle Scholar
  15. 15.
    Lubetsky JB, Dios A, Han J, Aljabari B, Ruzsicska B, Mitchell R, Lolis E, Al-Abed Y (2002) The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem 277:24976–24982PubMedCrossRefGoogle Scholar
  16. 16.
    Senter PD, Al-Abed Y, Metz CN, Benigni F, Mitchell RA, Chesney J, Han J, Gartner CG, Nelson SD, Todaro GJ, Bucala R (2002) Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc Natl Acad Sci USA 99:144–149PubMedCrossRefGoogle Scholar
  17. 17.
    Orita M, Yamamoto S, Katayama N, Aoki M, Takayama K, Yamagiwa Y, Seki N, Suzuki H, Kurihara H, Sakashita H, Takeuchi M, Fujita S, Yamada T, Tanaka A (2001) Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography. J Med Chem 44:540–547PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang X, Bucala R (1999) Inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity by dopachrome analogs. Bioorg Med Chem Lett 9:3193–3198PubMedCrossRefGoogle Scholar
  19. 19.
    Dios A, Mitchell RA, Aljabari B, Lubetsky J, O’Connor K, Liao H, Senter PD, Manogue KR, Lolis E, Metz C, Bucala R, Callaway DJ, Al-Abed Y (2002) Inhibition of MIF bioactivity by rational design of pharmacological inhibitors of MIF tautomerase activity. J Med Chem 45:2410–2416PubMedCrossRefGoogle Scholar
  20. 20.
    Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y (2007) Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor. J Biol Chem 282:23089–23095PubMedCrossRefGoogle Scholar
  21. 21.
    Dabideen DR, Cheng KF, Aljabari B, Miller EJ, Pavlov VA, Al-Abed Y (2007) Phenolic hydrazones are potent inhibitors of macrophage migration inhibitory factor proinflammatory activity and survival improving agents in sepsis. J Med Chem 5:1993–1997CrossRefGoogle Scholar
  22. 22.
    Al-Abed Y, Dabideen D, Aljabari B, Valster A, Messmer D, Ochani M, Tanovic M, Ochani K, Bacher M, Nicoletti F, Metz C, Pavlov VA, Miller EJ, Tracey KJ (2005) ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol Chem 280:36541–36544PubMedCrossRefGoogle Scholar
  23. 23.
    Cheng KF, Al-Abed Y (2006) Critical modifications of the ISO-1 scaffold improve its potent inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity. Bioorg Med Chem Lett 16:3376–3379PubMedCrossRefGoogle Scholar
  24. 24.
    Cournia Z, Leng L, Gandavadi S, Du X, Bucala R, Jorgensen WL (2009) Discovery of human macrophage migration inhibitory factor (MIF)-CD74 antagonists via virtual screening. J Med Chem 52:416–424PubMedCrossRefGoogle Scholar
  25. 25.
    Winner M, Meier J, Zierow S, Rendon BE, Crichlow GV, Riggs R, Bucala R, Leng L, Smith N, Lolis E, Trent JO, Mitchell RA (2008) A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res 68:7253–7257PubMedCrossRefGoogle Scholar
  26. 26.
    Brown KK, Blaikie FH, Smith RA, Tyndall JD, Lue H, Bernhagen J, Winterbourn CC, Hampton MB (2009) Direct modification of the proinflammatory cytokine macrophage migration inhibitory factor by dietary isothiocyanates. J Biol Chem 284:32425–32433PubMedCrossRefGoogle Scholar
  27. 27.
    Langcake P, Pryce RJ (1977) A new class of phytoalexins from grapevines. Experientia 33:151–152PubMedCrossRefGoogle Scholar
  28. 28.
    Hain R, Bieseler B, Kindl H, Schroder G, Stocker R (1990) Expression of a stilbene synthase gene in Nicotiana tabacum results in synthesis of the phytoalexin resveratrol. Plant Mol Biol 15:325–335PubMedCrossRefGoogle Scholar
  29. 29.
    Soleas GJ, Diamandis EP, Goldberg DM (1997) Resveratrol: a molecule whose time has come? And gone? Clin Biochem 30:91–113PubMedCrossRefGoogle Scholar
  30. 30.
    Goldberg DM, Tsang E, Karumanchiri A, Diamandis E, Soleas G, Ng E (1996) Method to assay the concentrations of phenolic constituents of biological interest in wines. Anal Chem 68:1688–1694PubMedCrossRefGoogle Scholar
  31. 31.
    Mahyar-Roemer M, Katsen A, Mestres P, Roemer K (2001) Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse. Int J Cancer 94:615–622PubMedCrossRefGoogle Scholar
  32. 32.
    Tinhofer I, Bernhard D, Senfter M, Anether G, Loeffler M, Kroemer G, Kofler R, Csordas A, Greil R (2001) Resveratrol, a tumor-suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl-2. Faseb J 15:1613–1615PubMedGoogle Scholar
  33. 33.
    Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220PubMedCrossRefGoogle Scholar
  34. 34.
    Pervaiz S (2003) Resveratrol: from grapevines to mammalian biology. Faseb J 17:1975–1985PubMedCrossRefGoogle Scholar
  35. 35.
    Stivala LA, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi E, Vannini V (2001) Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J Biol Chem 276:22586–22594PubMedCrossRefGoogle Scholar
  36. 36.
    Matsuoka A, Takeshita K, Furuta A, Ozaki M, Fukuhara K, Miyata N (2002) The 4′-hydroxy group is responsible for the in vitro cytogenetic activity of resveratrol. Mutat Res 521:29–35PubMedCrossRefGoogle Scholar
  37. 37.
    Murias M, Handler N, Erker T, Pleban K, Ecker G, Saiko P, Szekeres T, Jager W (2004) Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship. Bioorg Med Chem 12:5571–5578PubMedCrossRefGoogle Scholar
  38. 38.
    Pagliai F, Pirali T, Del Grosso E, Di Brisco R, Tron GC, Sorba G, Genazzani AA (2006) Rapid synthesis of triazole-modified resveratrol analogues via click chemistry. J Med Chem 49:467–470PubMedCrossRefGoogle Scholar
  39. 39.
    Wang Z, Hsieh TC, Zhang Z, Ma Y, Wu JM (2004) Identification and purification of resveratrol targeting proteins using immobilized resveratrol affinity chromatography. Biochem Biophys Res Commun 323:743–749PubMedCrossRefGoogle Scholar
  40. 40.
    Tanaka K, Arao T, Maegawa M, Matsumoto K, Kaneda H, Kudo K, Fujita Y, Yokote H, Yanagihara K, Yamada Y, Okamoto I, Nakagawa K, Nishio K (2009) SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion. Int J Cancer 124:1072–1080PubMedCrossRefGoogle Scholar
  41. 41.
    Pozo-Guisado E, Lorenzo-Benayas MJ, Fernandez-Salguero PM (2004) Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation. Int J Cancer 109:167–173PubMedCrossRefGoogle Scholar
  42. 42.
    Li Y, Liu J, Liu X, Xing K, Wang Y, Li F, Yao L (2006) Resveratrol-induced cell inhibition of growth and apoptosis in MCF7 human breast cancer cells are associated with modulation of phosphorylated Akt and caspase-9. Appl Biochem Biotechnol 135:181–192PubMedCrossRefGoogle Scholar
  43. 43.
    Pozo-Guisado E, Alvarez-Barrientos A, Mulero-Navarro S, Santiago-Josefat B, Fernandez-Salguero PM (2002) The antiproliferative activity of resveratrol results in apoptosis in MCF-7 but not in MDA-MB-231 human breast cancer cells: cell-specific alteration of the cell cycle. Biochem Pharmacol 64:1375–1386PubMedCrossRefGoogle Scholar
  44. 44.
    Tang HY, Shih A, Cao HJ, Davis FB, Davis PJ, Lin HY (2006) Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. Mol Cancer Ther 5:2034–2042PubMedCrossRefGoogle Scholar
  45. 45.
    Gehm BD, McAndrews JM, Chien PY, Jameson JL (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 94:14138–14143PubMedCrossRefGoogle Scholar
  46. 46.
    Joe AK, Liu H, Suzui M, Vural ME, Xiao D, Weinstein IB (2002) Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res 8:893–903PubMedGoogle Scholar
  47. 47.
    Murias M, Jager W, Handler N, Erker T, Horvath Z, Szekeres T, Nohl H, Gille L (2005) Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure-activity relationship. Biochem Pharmacol 69:903–912PubMedCrossRefGoogle Scholar
  48. 48.
    Leech M, Metz C, Bucala R, Morand EF (2000) Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis. Arthritis Rheum 43:827–833PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yoshihiko Fujita
    • 1
  • Rafiqul Islam
    • 2
  • Kazuko Sakai
    • 1
  • Hiroyasu Kaneda
    • 1
  • Kanae Kudo
    • 1
  • Daisuke Tamura
    • 1
  • Keiichi Aomatsu
    • 1
  • Tomoyuki Nagai
    • 1
  • Hidekazu Kimura
    • 1
  • Kazuko Matsumoto
    • 1
  • Marco A. de Velasco
    • 1
  • Tokuzo Arao
    • 1
  • Tadashi Okawara
    • 2
  • Kazuto Nishio
    • 1
    Email author
  1. 1.Department of Genome BiologyKinki University School of MedicineOsakaJapan
  2. 2.Institute of Health ScienceKumamoto Health Science UniversityKumamotoJapan

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