Abstract
N-Acetyl-d-glucosamine-substituted glycoconjugates (GCJs) with the polyamidoamine (GN8P) or calix[4]arene (GN4C) scaffold represent ligands for NKR-P1 molecule and induce NK cell-mediated cytotoxicity in vitro. The in vivo effect of these GCJs on mouse melanoma model was determined when administered either alone or in combination with non-specific immunostimulator keyhole limpet hemocyanin (KLH). All types of treatment significantly reduced the tumor growth on day 23, while GN4C as well as KLH were effective continuously (from day 14). The GN4C also induced the longest mean survival time (46.3 ± 11.1 d), followed by KLH+GN4C (36.4 ± 12.1), KLH (35.6 ± 6.5), KLH+GN8P (35.6 ± 6.7), and GN8P (32.4 ± 7.0), compared to controls (29.8 ± 3.6). The B16F10 specific cytotoxicity of peripheral blood cells was significantly elevated by both KLH and GN8P, whereas not by GN4C. KLH increased the effect of the GN4C, but did not influence that of GN8P. GN4C was proved to exert anticancer activity in mouse melanoma model. The combination of KLH with GCJs did not generate synergism.
Similar content being viewed by others
Abbreviations
- CTL:
-
cytotoxic T lymphocyte
- EGFR1:
-
epithelial growth factor receptor 1
- GlcNAc:
-
N-acetyl-d-glucosamine
- GCJ(s):
-
glycoconjugate(s)
- GN4C:
-
N-acetyl-d-glucosamine-substituted calix[4]arene
- GN8P:
-
N-acetyl-d-glucosamine-substituted polyamidoamine dendrimer
- IFN:
-
interferon
- IL:
-
interleukin
- KLH:
-
keyhole limpet hemocyanin
- NK:
-
natural killer
- NKR-P1:
-
natural killer cell receptor protein 1
- NKT:
-
natural killer T cell
- PBCs:
-
peripheral blood cells
- PBMCs:
-
peripheral blood mononuclear cells
References
Benson V., Grobarova V., Richter J., Fiserova A.: Glycosylation regulates NK cell-mediated effector function through PI3K pathway. Internat.Immunol., in press (2010).
Bezouska K.: Design, functional evaluation and biomedical applications of carbohydrate dendrimers (glycodendrimers). J.Biotechnol.90, 269–290 (2002).
Bezouska K., Yuen C.T., O’Brien J., Childs R.A., Chai W., Lawson A.M., Drbal K., Fiserova A., Pospisil M., Feizi T.: Oligosaccharide ligands for NKR-P1 protein activate NK cells and cytotoxicity. Nature372, 150–157 (1994).
Bezouska K., Snajdrova R., Krenek K., Vancurova M., Kadek A., Adamek D., Lhotak P., Kavan D., Hofbauerova K., Man P., Bojarova P., Kren V.: Carboxylated calixarenes bind strongly to CD69 and protect CD69+ killer cells from suicidal cell death induced by tumor cell surface ligands. Bioorg.Med.Chem.18, 1434–1440 (2010).
Fiserova A., Starec M., Kuldova M., Kovaru H., Pav M., Vannucci L., Pospisil M.: Effects of D2-dopamine and α-adrenoreceptor antagonists in stress induced changes on immune responsiveness of mice. J.Neuroimmunol.130, 55–65 (2002).
Harris J.R., Markl J.: Keyhole limpet hemocyanin (KLH): a biomedical review. Micron30, 597–623 (1999).
Hulikova K., Benson A., Svoboda J., Sima P., Fiserova A.: N-Acetyl-d-glucosamine-coated polyamidoamine dendrimer modulates antibody formation via natural killer cell activation. Internat.Immunopharmacol.9, 792–799 (2009).
Jurincic-Winkler C.D., Metz K.A., Beuth J., Klippel K.F.: Keyhole limpet hemocyanin for carcinoma in situ of the bladder: a longterm follow-up study. Eur.Urol.37, 45–49 (2000).
Krenek K., Kuldova M., Hulikova K., Stibor I., Lhotak P., Dudic M., Budka J., Pelantova H., Bezouska K., Fiserova A., Kren V.: N-Acetyl-d-glucosamine substituted calix[4]arenes as stimulators of NK cell-mediated antitumor immune response. Carbohydr.Res.342, 1781–1792 (2007).
Kuldová M., Svoboda J., Kovářů F., Vannucci L., Kovářů H., Fišerová A.: NK cell-mediated cytotoxicity modulation by A2 adenosine receptor agonist in different mammalian species. Folia Microbiol.54, 364–368 (2009).
Lanier L.L.: NK cell recognition. Ann.Rev.Immunol.23, 225–274 (2005).
Lindhorst T.K., Kieburg C.: Glycocoating of oligovalent amines: synthesis of thiourea-bridged cluster glycosides from glycosyl isothiocyanates. Agnew.Chem. Internat.Ed.Engl.35, 1953–1956 (1996).
Lindhorst T.K.: Artificial multivalent sugar ligands to understand and manipulate carbohydrate-protein interactions. Host-Guest Chem.218, 201–235 (2002).
Mcfadden D.W., Riggs D.R., Jackson B.J., Vona-Davis L.: Keyhole limpet hemocyanin, a novel immune stimulant with promising anticancer activity in Barrett’s oesophageal adenocarcinoma. Am.J.Surg.186, 552–555 (2003).
Mcfadden D.W., Riggs D.R., Jackson B.J., Ng A., Cunningham C.: Keyhole limpet hemocyanin potentiates standard immunotherapy for melanoma. Am.J.Surg.193, 284–287 (2007).
Pospisil M., Vannucci L., Fiserova A., Sadalapure K., Krausova K., Horvath O., Kren V., Mosca F., Lindhorst T.K., Bezouska K.: Glycodendrimeric ligands of C-type lectin receptors as therapeutic agents in experimental cancer. Adv.Exp Med.Biol.495, 343–348 (2001).
Riggs D.R., Jackson B.S., Vona-Davis L., Mcfadden D.: In vitro anticancer effects of a novel immunostimulant: keyhole limpet hemocyanin. J.Surg.Res.108, 279–284 (2002)
Rizvi I., Riggs D.R., Jakson B.J., Mcfadden D.W.: Keyhole limpet hemocyanin: an effective adjunct against melanoma in vivo. Am.J.Surg.194, 628–632 (2007).
Vannucci L., Fiserova A., Sadalapure K., Lindhorst T.K., Kuldova M., Rossman P., Horvath O., Kren V., Krist P., Bezouska K., Luptovcova M., Mosca F., Pospisil M.: Effects of N-acetyl-glucosamine-coated glycodendrimers as biological modulators in the B16F10 melanoma model in vivo. Internat.J.Oncol.23, 285–296 (2003).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hulíková, K., Grobárová, V., Křivohlavá, R. et al. Antitumor activity of N-acetyl-d-glucosamine-substituted glycoconjugates and combined therapy with keyhole limpet hemocyanin in B16F10 mouse melanoma model. Folia Microbiol 55, 528–532 (2010). https://doi.org/10.1007/s12223-010-0087-5
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12223-010-0087-5