Molecular Biology

, Volume 52, Issue 2, pp 262–268 | Cite as

Novel Glycyrrhetinic Acid Derivative Soloxolone Methyl Inhibits the Inflammatory Response and Tumor Growth in vivo

  • A. V. Markov
  • A. V. Sen’kova
  • M. A. Zenkova
  • E. B. Logashenko
Molecular Cell Biology
  • 2 Downloads

Abstract

Due to wide spreading of inflammatory disease and imperfection of available anti-inflammatory drugs, mainly associated with their serious side effects, searching for new anti-inflammatory agents is a pressing problem. Natural triterpenoids and their synthetic analogs are a promising source of new drugs. In this study, we have investigated the anti-inflammatory and antitumor effects in vivo of the glycyrrhetinic acid derivative soloxolone methyl (SM), or methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate. SM was shown to efficiently suppress the development of edema in a mouse model of carrageenan- or histamine- induced acute inflammation. SM also inhibited the tumor growth and reduced the tumor cell count in the ascitic fluid in mice bearing Krebs-2 carcinoma, the development of which is accompanied by an inflammatory process in the surrounding tissues.

Keywords

soloxolone methyl non-steroidal anti-inflammatory drugs triterpenoids glycyrrhetinic acid derivatives antitumor compounds cyano enone functionality 

Abbreviations

DMSO

dimethyl sulfoxide

LPS

lipopolysaccharide

NSAID

nonsteroidal anti-inflammatory drug

SM

soloxolone methyl

PBS

phosphate-buffered saline

COX-2

cyclooxygenase 2

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References

  1. 1.
    Loeb D.S., Ahlquist D.A., Talley N.J. 1992. Management of gastroduodenopathy associated with use of nonsteroidal anti-inflammatory drugs. Mayo Clin. Proc. 67, 354–364.CrossRefPubMedGoogle Scholar
  2. 2.
    Champion G.D., Feng P.H., Azuma T., et al. 1997. NSAID-induce gastrointestinal damage: Epidemiology, risk and prevention, with an evaluation of the role of misoprostol. An Asia-Pacific perspective and consensus. Drugs. 53, 6–19.PubMedGoogle Scholar
  3. 3.
    Nathan C., Ding A. 2010. Nonresolving inflammation. Cell. 140, 871–882.CrossRefPubMedGoogle Scholar
  4. 4.
    Coussens L.M., Werb Z. 2002. Inflammation and cancer. Nature. 420, 860–867.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Aggarwal B.B., Shishodia S., Sandur S.K., et al. 2006. Inflammation and cancer: How hot is the link? Biochem. Pharmacol. 72, 1605–1621.Google Scholar
  6. 6.
    Li J.Y., Cao H.Y., Liu P., et al. 2014. Glycyrrhizic acid in the treatment of liver diseases: Literature review. Biomed. Res. Int. 2014, 872139.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Pompei R., Laconi S., Ingianni A. 2009. Antiviral properties of glycyrrhizic acid and its semisynthetic derivatives. Mini-Rev. Med. Chem. 9, 996–1001.CrossRefPubMedGoogle Scholar
  8. 8.
    Roohbakhsh A., Iranshahy M., Iranshahi M. 2016. Glycyrrhetinic acid and its derivatives: Anti-cancer and cancer chemopreventive properties, mechanisms of action and structure-cytotoxic activity relationship. Curr. Med. Chem. 23, 498–517.CrossRefPubMedGoogle Scholar
  9. 9.
    Langer D., Czarczynska-Goslinska B., Goslinski T. 2016. Glycyrrhetinic acid and its derivatives in infectious diseases. Curr. Issues Pharm. Med. Sci. 29, 118–123.Google Scholar
  10. 10.
    Ming L.J., Yin A.C. 2013. Therapeutic effects of glycyrrhizic acid. Nat. Prod. Commun. 8, 415–418.PubMedGoogle Scholar
  11. 11.
    Grabowski P.S., Wright P.K., Van’t Hof R.J., et al. 1997. Immunolocalization of inducible nitric oxide synthase in synovium and cartilage in rheumatoid arthritis and osteoarthritis. Br. J. Rheumatol. 36, 651–655.CrossRefPubMedGoogle Scholar
  12. 12.
    Lallemand B., Gelbcke M., Dubois J., Prévost M., Jabin I., Kiss R. 2011. Structure–activity relationship analyses of glycyrrhetinic acid derivatives as anticancer agents. Mini-Rev. Med. Chem. 11, 881–887.CrossRefPubMedGoogle Scholar
  13. 13.
    Markov A.V., Zenkova M.A., Logashenko E.B. 2017. Modulation of tumour-related signaling pathways by natural pentacyclic triterpenoids and their semisynthetic derivatives. Curr. Med. Chem. 24, 1277–1320.CrossRefPubMedGoogle Scholar
  14. 14.
    Liby K.T., Sporn M.B. 2012. Synthetic oleanane triterpenoids: Multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64, 972–1003.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chintharlapalli S., Papineni S., Jutooru I., et al. 2007. Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor {gamma} agonists in colon cancer cells. Mol. Cancer Ther. 6, 1588–1598.CrossRefPubMedGoogle Scholar
  16. 16.
    Chadalapaka G., Jutooru I., McAlee A., et al. 2008. Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives. Bioorg. Med. Chem. Lett. 18, 2633–2639.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Logashenko E.B., Salomatina O.V., Markov A.V., et al. 2011. Synthesis and pro-apoptotic activity of novel glycyrrhetinic acid derivatives. ChemBioChem. 12, 784–794.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Popadyuk I.I., Markov A.V., Salomatina O.V., et al. 2015. Synthesis and biological activity of novel deoxycholic acid derivatives. Bioorg. Med. Chem. 23, 5022–5034.CrossRefPubMedGoogle Scholar
  19. 19.
    Guzik T.J., Korbut R., Adamek-Guzik T. 2003. Nitric oxide and superoxide in inflammation and immune regulation. J. Physiol. Pharmacol. 54, 469–487.PubMedGoogle Scholar
  20. 20.
    Salomatina O.V., Markov A.V., Logashenko E.B., et al. 2014. Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and NO production in LPS-activated J-774 cells. Bioorg. Med. Chem. 22, 585–593.CrossRefPubMedGoogle Scholar
  21. 21.
    Morris C.J. 2003. Carrageenan-induced paw edema in the rat and mouse. Methods Mol. Biol. 225, 115–121.PubMedGoogle Scholar
  22. 22.
    Gepdiremen A., Mshvildadze V., Suleyman H., et al. 2004. Acute and chronic antiinflammatory effects of Hedera colchica in rats. J. Ethnopharmacol. 94, 191–195.CrossRefPubMedGoogle Scholar
  23. 23.
    Perianayagam J.B., Sharma S.K., Pillai K.K. 2006. Anti-inflammatory activity of Trichodesma indicum root extract in experimental animals. J. Ethnopharmacol. 104, 410–414.CrossRefPubMedGoogle Scholar
  24. 24.
    Tubaro A., Dri P., Delbello G., et al. 1986. The croton oil ear test revisited. Agents Actions. 17, 347–349.CrossRefPubMedGoogle Scholar
  25. 25.
    Salvemini D., Wang Z.Q., Wyatt P.S., et al. 1996. Nitric oxide: A key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br. J. Pharmacol. 118, 829–838.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Radomski M.W., Palmer R.M., Moncada S. 1990. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc. Natl. Acad. Sci. U. S. A. 87, 5193–5197.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lee Y.M., Hirota S., Jippo-Kanemoto T., et al. 1996. Inhibition of histamine synthesis by glycyrrhetinic acid in mast cells cocultured with Swiss 3T3 fibroblasts. Int. Arch. Allergy Immunol. 110, 272–277.CrossRefPubMedGoogle Scholar
  28. 28.
    Imanishi N., Kawai H., Hayashi Y., et al. 1989. Effects of glycyrrhizin and glycyrrhetinic acid on dexamethasone-induced changes in histamine synthesis of mouse mastocytoma P-815 cells and in histamine release from rat peritoneal mast cells. Biochem. Pharmacol. 38, 2521–2526.CrossRefPubMedGoogle Scholar
  29. 29.
    Liu J. 1995. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol. 49, 57–68.CrossRefPubMedGoogle Scholar
  30. 30.
    Lee J.Y., Moon H., Kim C.J. 2010. Effects of hydroxy pentacyclic triterpene acids from Forsythia viridissima on asthmatic responses to ovalbumin challenge in conscious guinea pigs. Biol. Pharm. Bull. 33, 230–237.CrossRefPubMedGoogle Scholar
  31. 31.
    Hu L.N, Fang X.Y., Liu H.L., et al. 2013. Protective effects of 18ß-glycyrrhetinic acid on LPS-induced injury in intestinal epithelial cells. Chin. J. Nat. Med. 11, 24–29.CrossRefGoogle Scholar
  32. 32.
    Luo L., Jin Y., Kim I.D., Lee J.K. 2013. Glycyrrhizin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. Exp. Neurobiol. 22, 107–115.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Deeb D., Gao X., Jiang H., et al. 2009. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro-survival Akt and mTOR. Prostate. 69, 851–860.CrossRefPubMedGoogle Scholar
  34. 34.
    Fukumitsu S., Villareal M.O., Fujitsuka T., et al. 2016. Anti-inflammatory and anti-arthritic effects of pentacyclic triterpenoids maslinic acid through NF-kB inactivation. Mol. Nutr. Food Res. 60, 399–409.CrossRefPubMedGoogle Scholar
  35. 35.
    Kulkarni S.K., Mehta A.K., Kunchandy J. 1986. Antiinflammatory actions of clonidine, guanfacine and B HT 920 against various inflammagen-induced acute paw oedema in rats. Arch. Int. Pharmacodyn. Ther. 279, 324–334.PubMedGoogle Scholar
  36. 36.
    Nagy J.A., Benjamin L., Zeng H., et al. 2008. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis. 11, 109–119.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Rozenberg I., Sluka S.H., Rohrer L., et al. 2010. Histamine H1 receptor promotes atherosclerotic lesion formation by increase vascular permeability for low-density lipoproteins. Arterioscler. Thromb. Vasc. Biol. 30, 923–930.CrossRefPubMedGoogle Scholar
  38. 38.
    Yong Y.K., Zakaria Z.A., Kadir A.A., et al. 2013. Chemical constituents and antihistamine activity of Bixa orellana leaf extract. BMC Complementary Altern. Med. 13,32.CrossRefGoogle Scholar
  39. 39.
    Grivennikov S.I., Greten F.R., Karin M. 2010. Immunity, inflammation, and cancer. Cell. 140, 883–899.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Parsons D.F., Marko M., Braun S.J., et al. 1982. Ascites tumor invasion of mouse peritoneum studied by high-voltage electron microscope stereoscopy. Cancer Res. 42, 4574–4583.PubMedGoogle Scholar
  41. 41.
    Parsons D.F., Marko M., Wansor K.J. 1983. Inflammation with restricted lysosomal proteolysis during early ascites carcinoma invasion of mouse parietal peritoneum. A medium and high-voltage electron microscopic and cytochemical study. Tissue Cell. 15, 499–507.PubMedGoogle Scholar
  42. 42.
    Auletta J.J., Alabran J.L., Kim B.G., et al. 2010. The synthetic triterpenoid, CDDO-Me, modulates the proinflammatory response to in vivo lipopolysaccharide challenge. J. Interferon Cytokine Res. 30, 497–508.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Chen T., Mou Y., Tan J., et al. 2015. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. Int. Immunopharmacol. 25, 55–64.CrossRefPubMedGoogle Scholar
  44. 44.
    Wang Y.Y., Yang Y.X., Zhao R., et al. 2015. Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells. Drug Des., Dev. Ther. 9, 993–1026.Google Scholar
  45. 45.
    To C., Kulkarni S., Pawson T., et al. 2008. The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid-imidazolide alters transforming growth factor beta-dependent signaling and cell migration by affecting the cytoskeleton and the polarity complex. J. Biol. Chem. 283, 11700–11713.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sogno I., Vannini N., Lorusso G., et al. 2009. Antiangiogenic activity of a novel class of chemopreventive compounds: Oleanic acid terpenoids. Recent Results Cancer Res. 181, 209–212.CrossRefPubMedGoogle Scholar
  47. 47.
    Ball M.S., Shipman E.P., Kim H., et al. 2016. CDDOMe redirects activation of breast tumor associated macrophages. PLoS One. 11, e0149600.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Rayburn E.R., Ezell S.J., Zhang R. 2009. Anti-inflammatory agents for cancer therapy. Mol. Cell. Pharmacol. 1, 29–43.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • A. V. Markov
    • 1
  • A. V. Sen’kova
    • 1
  • M. A. Zenkova
    • 1
  • E. B. Logashenko
    • 1
  1. 1.Institute of Chemical Biology and Fundamental Medicine, Siberian BranchRussian Academy of SciencesNovosibirskRussia

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