Advertisement

Tumor Biology

, Volume 37, Issue 8, pp 11349–11358 | Cite as

Oligoesculin fraction induces anti-tumor effects and promotes immune responses on B16-F10 mice melanoma

  • Imen Mokdad Bzeouich
  • Nadia Mustapha
  • Aicha Sassi
  • Kamel Ghedira
  • Mohamed Ghoul
  • Latifa Chebil
  • José Luis
  • Leila Chekir-Ghedira
Original Article

Abstract

Laccase was used to enzymatically polymerize esculin. Oligoesculin fraction was obtained after ultrafiltration through a 5-kDa membrane. Several studies have been carried out to prove the effectiveness of natural substances such as immunomodulators to promote the anti-cancer activity in situ. The purpose of our report was to explore whether the anti-tumor potential of the oligoesculin fraction in vitro and in vivo is linked to its immunological mechanisms in melanoma-bearing mice. We revealed that oligoesculin fraction reduced B16-F10 proliferation and migration in vitro in a dose-related manner. Moreover, melanin synthesis and tyrosinase activity were inhibited in these melanoma cells in a concentration-dependent way. The anti-tumor potential of oligoesculin fraction was also assessed in vivo. Our results showed that intraperitoneal administration of oligoesculin fraction, at 50 mg/kg body weight (b.w.) for 21 days, reduced tumor size and weight with percentages of inhibition of 94 and 87 %, respectively. Oligoesculin fraction was effective in promoting lysosomal activity and nitric oxide (NO) production by peritoneal macrophages in tumor-implanted mice. In addition, the activities of natural killer (NK), cytotoxic T lymphocytes, and macrophages were significantly enhanced by oligoesculin fraction. These findings suggested that this polymer with its anti-tumor and immunomodulatory properties could be used for the treatment of melanoma.

Keywords

Oligoesculin fraction Melanoma Migration Immunomodulatory effect Anti-tumor activity 

Notes

Acknowledgments

We acknowledge the “Ministère Tunisien de l’enseignement supérieur et de la recherche scientifique” for the financial support of this study.

Compliance with ethical standards

All experiments were performed in accordance with guidelines for the care and use of laboratory animals as published by the National Institute of Health (USA). All experiments received the explicit approval of the Ethics Animal Committee in Tunisia.

References

  1. 1.
    Navarini AL, Chiaradia LD, Mascarello A, Fritzen M, Nunes RJ, Yunes RA, et al. Hydroxychalcones induce apoptosis in B16F10 melanoma cells via GSH and ATP depletion. Eur J Med Chem. 2009;44:1630–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Kim KD, Choi SC, Kim A, Choe YK, Choe IS, Lim JS. Dendritic cell-tumor coculturing vaccine can induce antitumor immunity through both NK and CTL interaction. Int Immunopharmacol. 2001;1:2117–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Liu X, Zhao M, Wu K, Chai X, Yu H, Tao Z, et al. Immunomodulatory and anticancer activities of phenolics from emblica fruit (Phyllanthus emblica L.). Food Chem. 2012;131:685–90.CrossRefGoogle Scholar
  4. 4.
    Bubols GB, Vianna Dda R, Medina-Remon A, von Poser G, Lamuela-Raventos RM, Eifler-Lima VL, et al. The antioxidant activity of coumarins and flavonoids. Mini Rev Med Chem. 2013;13:318–34.PubMedGoogle Scholar
  5. 5.
    Huang GJ, Deng JS, Liao JC, Hou WC, Wang SY, Sung PJ, et al. Inducible nitric oxide synthase and cyclooxygenase-2 participate in anti-inflammatory activity of imperatorin from Glehnia littoralis. J Agric Food Chem. 2012;60:1673–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Kostova I. Coumarins as inhibitors of HIV reverse transcriptase. Curr HIV Res. 2006;4:347–63.CrossRefPubMedGoogle Scholar
  7. 7.
    Golfakhrabadi F, Abdollahi M, Ardakani MRS, Saeidnia S, Akbarzadeh T, Ahmadabadi AN, et al. Anticoagulant activity of isolated coumarins (suberosin and suberenol) and toxicity evaluation of Ferulago carduchorum in rats. Pharm Biol. 2014;52:1335–40.CrossRefPubMedGoogle Scholar
  8. 8.
    de Souza SM, Delle Monache F, Smânia Jr A. Antibacterial activity of coumarins. Z Naturforsch C. 2005;60:693–700.CrossRefPubMedGoogle Scholar
  9. 9.
    Nasr T, Bondock S, Youns M. Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives. Eur J Med Chem. 2014;76:539–48.CrossRefPubMedGoogle Scholar
  10. 10.
    Hollmann F, Arends IWCE. Enzyme initiated radical polymerizations. Polymers. 2012;4:759–93.CrossRefGoogle Scholar
  11. 11.
    Jeon JK, Baldrian P, Murugesan K, Chang YS. Laccase-catalysed oxidations of nat-urally occuring phenols: from in vivo biosynthetic pathways to green synthetic applications. Microb Biotechnol. 2012;5:318–32.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rios ER, Rocha NF, Venâncio ET, Moura BA, Feitosa ML, Cerqueira GS, et al. Mechanisms involved in the gastroprotective activity of esculin on acute gastric lesions in mice. Chem Biol Interact. 2010;188:246–54.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhao DL, Zou LB, Lin S, Shi JG, Zhu HB. Anti apoptotic effect of esculin on dopamine-induced cytotoxicity in the human neuroblastoma SH SY5Y cell line. Neuropharmacology. 2007;53:724–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Stefanova Z, Neychev H, Ivanovska N, Kostova I. Effect of a total extract from Fraxinus ornus stem bark and esculin on zymosan- and carrageenan-induced paw oedema in mice. J Ethnopharmacol. 1995;46:101–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Anthoni J, Humeau C, Rose Maia E, Chebil L, Engasser J, Ghoul M. Enzymatic synthesis of oligoesculin: structure and biological activities characterizations. Eur Food Res Technol. 2010;23:571–9.CrossRefGoogle Scholar
  16. 16.
    Ben Rhouma G, Chebil L, Krifa M, Ghoul M, Chekir-Ghedira L. Evaluation of mutagenic and antimutagenic activities of oligorutin and oligoesculin. Food Chem. 2012;135:1700–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Mokdad-Bzeouich I, Mustapha N, Chaabane F, Ghedira Z, Ghedira K, Ghoul M, et al. Oligomerization of esculin improves its antibacterial activity and modulates antibiotic resistance. J Antibiot. 2015;68:148–52.CrossRefPubMedGoogle Scholar
  18. 18.
    Faix O, Lange W, Salud EC. The Use of HPLC for the Determination of Average Molecular Weights and Molecular Weight Distributions of Milled Wood Lignins from Shorea polysperma (Blco.). Holzforschung. 1981;35:3–9.CrossRefGoogle Scholar
  19. 19.
    Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;655:5–63.Google Scholar
  20. 20.
    Ding M, Feng R, Wang SY, Bowman L, Lu Y, Qian Y, et al. Cyanidin-3-glucoside, a natural product derived from blackberry, exhibits chemopreventive and chemotherapeutic activity. J Biol Chem. 2006;281:17359–68.CrossRefPubMedGoogle Scholar
  21. 21.
    Skandrani I, Pinon A, Simon A, Ghedira K, Chekir-Ghedira L. Chloroform extract from Moricandia arvensis inhibits growth of B16-F0 melanoma cells and promotes differentiation in vitro. Cell Prolif. 2010;43:471–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Manosroi A, Saraphanchotiwitthaya A, Manosroi J. In vitro immunomodulatory effect of Pouteria cambodiana (Pierre ex Dubard) Baehni extract. J Ethnopharmacol. 2005;101:90–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Yoon WJ, Kim SS, Oh TH, Lee NH, Hyun CG. Abies koreana essential oil inhibits drug-resistant skin pathogen growth and LPS-induced inflammatory effects of murine macrophage. Lipids. 2009;44:471–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Sarangi I, Ghosh D, Bhutia SK, Mallick SK, Maiti TK. Anti-tumor and immunomodulating effects of Pleurotus ostreatus mycelia-derived proteogly-cans. Int Immunopharmacol. 2006;6:1287–97.CrossRefPubMedGoogle Scholar
  25. 25.
    Cottrell BJ, Pye C, Glauert AM, Butterworth AE. Human macrophage-mediated cytotoxicity of Schistosoma mansoni. Functional and structural features of the effector cells. J Cell Sci. 1987;94:733–41.Google Scholar
  26. 26.
    de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6:24–37.CrossRefPubMedGoogle Scholar
  27. 27.
    Kawaii S, Tomono Y, Ogawa K, Sugiura M, Yano M, Yoshizawa Y, et al. Antiproliferative effect of isopentenylated coumarins on several cancer cell lines. Anticancer Res. 2001;21:1905–11.PubMedGoogle Scholar
  28. 28.
    Jiménez-Orozco FA, Molina-Guarneros JA, Mendoza-Patiño N, León-Cedeño F, Flores-Pérez B, Santos-Santos E, et al. Cytostatic activity of coumarin metabolites and derivatives in the B16-F10 murine melanoma cell line. Melanoma Res. 1999;9:243–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Brooks PC. Cell adhesion molecules in angiogenesis. Cancer Metastasis Rev. 1996;15:187–94.CrossRefPubMedGoogle Scholar
  30. 30.
    Mokdad-Bzeouich I, Kovacic H, Ghedira K, Chebil L, Ghoul M, Chekir-Ghedira L, Luis J. Esculin and its oligomer fractions inhibit adhesion and migration of U87 glioblastoma cells and in vitro angiogenesis. Tumor Biol; 2015.DOI  10.1007/s13277-015-4209-1
  31. 31.
    Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev. 2004;84:1155–228.CrossRefPubMedGoogle Scholar
  32. 32.
    Slominski A, Zmijewski MA, Pawelek J. L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocyte functions. Pigment Cell Melanoma Res. 2011;25:14–27.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Slominski AT, Carlson JA. Melanoma resistance: a bright future for academicians and a challenge for patient advocates. Mayo Clin Proc. 2014;89:429–33.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Slominski A, Paus R, Mihm MC. Inhibition of melanogenesis as an adjuvant strategy in the treatment of melanotic melanomas: selective review and hypothesis. Anticancer Res. 1998;18:3709–15.PubMedGoogle Scholar
  35. 35.
    Slominski A, Zbytek B, Slominski R. Inhibitors of melanogenesis increase toxicity of cyclophosphamide and lymphocytes against melanoma cells. Int J Cancer. 2009;124:1470–7.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Slominski RM, Zmijewski MA, Slominski AT. The role of melanin pigment in melanoma. Exp Dermatol. 2015;24:258–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hong YD, Nam MH, Lee CS, Shin SS, Park YH. Depigmenting Effects of Esculetin and Esculin Isolated from Fraxinus rhynchophylla Hance. J Soc Cosmet. 2013;40:89–94.Google Scholar
  38. 38.
    Wang J, Lu ML, Dai HL, Zhang SP, Wang HX, Wei N. Esculetin, a coumarin derivative, exerts in vitro and in vivo antiproliferative activity against hepatocellular carcinoma by initiating a mitochondrial-dependent apoptosis pathway. Braz J Med Biol Res. 2015;48:245–53.CrossRefPubMedGoogle Scholar
  39. 39.
    Kayser O, Kolodziej H, Kiderlen AF. Immunomodulatory principles of Pelargonium sidoides. Phytother Res. 2001;15:122–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Gough NR. Natural Killer Cells on the Attack. Sci Signal. 2014;7:84.CrossRefGoogle Scholar
  41. 41.
    Moretta L, Bottino C, Cantoni C, Mingari MC, Moretta A. Human natural killer cell function and receptors. Curr Opin Pharmacol. 2001;1:387–91.CrossRefPubMedGoogle Scholar
  42. 42.
    Leung KN, Leung PY, Kong LP, Leung PK. Immunomodulatory effects of esculetin (6,7-dihydroxycoumarin) on murine lymphocytes and peritoneal macrophages. Cell Mol Immunol. 2005;2:181–8.PubMedGoogle Scholar
  43. 43.
    Dumont S, Hartmann D, Poindron P, Oberling F, Faradji A, Bartholeyns J. Control of antitumoral activity of human macrophages produced in large amounts in view of adoptive transfer. Eur J Cancer Clin Oncol. 1985;24:1691.CrossRefGoogle Scholar
  44. 44.
    Russell SW, Doe WF, McIntosh AT. Functional characterization of a stable non lytic stage of macrophage activation in tumors. J Exp Med. 1977;146:1511.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Imen Mokdad Bzeouich
    • 1
    • 2
  • Nadia Mustapha
    • 1
    • 2
  • Aicha Sassi
    • 1
    • 2
  • Kamel Ghedira
    • 2
  • Mohamed Ghoul
    • 3
  • Latifa Chebil
    • 3
  • José Luis
    • 4
  • Leila Chekir-Ghedira
    • 1
    • 2
  1. 1.Laboratory of Cellular and Molecular Biology. Faculty of Dental MedicineUniversity of MonastirMonastirTunisia
  2. 2.Unit of Bioactive and Natural Substances and Biotechnology UR12ES12. Faculty of PharmacyUniversity of MonastirMonastirTunisia
  3. 3.Laboratory of Biomolecular Engineering, National School of Agronomy and Food IndustriesNational Polytechnics Institute of Lorraine ENSAIA-INPLVandoeuvre les NancyFrance
  4. 4.INSERM UMR 911-CRO2, Faculty of PharmacyAix-Marseille UniversityMarseilleFrance

Personalised recommendations