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Published in: BMC Immunology 1/2014

Open Access 01-12-2014 | Research article

Anti-cancer properties of gastropodan hemocyanins in murine model of colon carcinoma

Authors: Vera Gesheva, Stela Chausheva, Nikolina Mihaylova, Iliyan Manoylov, Lyuba Doumanova, Krassimira Idakieva, Andrey Tchorbanov

Published in: BMC Immunology | Issue 1/2014

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Abstract

Background

Various immunotherapeutic approaches have been used for the treatment of cancer. A number of natural compounds are designed to repair, stimulate, or enhance the immune system response. Among them are the hemocyanins (Hcs) - extracellular copper proteins isolated from different arthropod and mollusc species. Hcs are oxygen transporter molecules and normally are freely dissolved in the hemolymph of these animals. Hemocyanins are very promising class of anti-cancer therapeutics due to their immunogenic properties and the absence of toxicity or side effects. KLH (Megathura crenulata hemocyanin) is the most studied molecule of this group setting a standard for natural carrier protein for small molecules and has been used in anti-tumor clinical trials.

Results

The Hcs isolated from marine snail Rapana thomasiana (RtH) and the terrestrial snail Helix pomatia (HpH) express strong in vivo anti-cancer and anti-proliferative effects in the developed by us murine model of colon carcinoma. The immunization with RtH and HpH prolonged the survival of treated animals, improve humoral anti-cancer response and moderate the manifestation of C-26 carcinoma symptoms as tumor growth, splenomegaly and lung metastasis appearance.

Conclusion

Hemocyanins are used so far for therapy of superficial bladder cancer and murine melanoma models. Our findings demonstrate a potential anti-cancer effect of hemocyanins on a murine model of colon carcinoma suggesting their use for immunotherapy of different types of cancer.
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Literature
1.
2.
go back to reference Morales A, Eidinger D, Bruce A: Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976, 116: 180-183.PubMed Morales A, Eidinger D, Bruce A: Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976, 116: 180-183.PubMed
3.
go back to reference Alexandroff A, Jackson A, O Donnell M, James K: BCG immunotherapy is used to prevent and treat superficial bladder cancer. BCG immunotherapy of bladder cancer: 20 years on. Lancet. 1999, 353: 1689-1694. 10.1016/S0140-6736(98)07422-4.PubMedCrossRef Alexandroff A, Jackson A, O Donnell M, James K: BCG immunotherapy is used to prevent and treat superficial bladder cancer. BCG immunotherapy of bladder cancer: 20 years on. Lancet. 1999, 353: 1689-1694. 10.1016/S0140-6736(98)07422-4.PubMedCrossRef
4.
go back to reference Scott A, Wolcho J, Old L: Antibody therapy of cancer. Nat Rev Cancer. 2012, 12: 278-287. 10.1038/nrc3236.PubMedCrossRef Scott A, Wolcho J, Old L: Antibody therapy of cancer. Nat Rev Cancer. 2012, 12: 278-287. 10.1038/nrc3236.PubMedCrossRef
5.
go back to reference Lee S, Margolin K: Cytokines in cancer immunotherapy. Cancer. 2011, 3: 3856-3893. 10.3390/cancers3043856.CrossRef Lee S, Margolin K: Cytokines in cancer immunotherapy. Cancer. 2011, 3: 3856-3893. 10.3390/cancers3043856.CrossRef
6.
go back to reference Small E, Schellhammer P, Higano C, Redfern C, Nemunaitis J, Valone F, Verjee S, Jones L, Hershberg R: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006, 24: 3089-3094. 10.1200/JCO.2005.04.5252.PubMedCrossRef Small E, Schellhammer P, Higano C, Redfern C, Nemunaitis J, Valone F, Verjee S, Jones L, Hershberg R: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006, 24: 3089-3094. 10.1200/JCO.2005.04.5252.PubMedCrossRef
7.
go back to reference Sabbatini P, Kudryashov V, Ragupathi G, Danishefsky SJ, Livingston PO, Bornmann W, Spassova M, Zatorski A, Spriggs D, Aghajanian C, Soignet S, Peyton M, O Flaherty C, Curtin JO, Lloyd K: Immunization of ovarian cancer patients with a synthetic lewisy-protein conjugate vaccine: clinical and serological results. Int J Cancer. 2000, 87: 79-85. 10.1002/1097-0215(20000701)87:1<79::AID-IJC12>3.0.CO;2-L.PubMedCrossRef Sabbatini P, Kudryashov V, Ragupathi G, Danishefsky SJ, Livingston PO, Bornmann W, Spassova M, Zatorski A, Spriggs D, Aghajanian C, Soignet S, Peyton M, O Flaherty C, Curtin JO, Lloyd K: Immunization of ovarian cancer patients with a synthetic lewisy-protein conjugate vaccine: clinical and serological results. Int J Cancer. 2000, 87: 79-85. 10.1002/1097-0215(20000701)87:1<79::AID-IJC12>3.0.CO;2-L.PubMedCrossRef
8.
go back to reference Ragupathi G, Slovin S, Adluri S, Sames D, Kim IJ, Kim HM, Spassova M, Bornmann WG, Lloyd KO, Scher HI, Livingston PO, Danishefsky SJ: A fully synthetic globo H carbohydrate vaccine induces a focused humoral response in prostate cancer patients: a proof of principle. Angew Chem Int Ed Engl. 1999, 38: 563-566. 10.1002/(SICI)1521-3773(19990215)38:4<563::AID-ANIE563>3.0.CO;2-3.CrossRef Ragupathi G, Slovin S, Adluri S, Sames D, Kim IJ, Kim HM, Spassova M, Bornmann WG, Lloyd KO, Scher HI, Livingston PO, Danishefsky SJ: A fully synthetic globo H carbohydrate vaccine induces a focused humoral response in prostate cancer patients: a proof of principle. Angew Chem Int Ed Engl. 1999, 38: 563-566. 10.1002/(SICI)1521-3773(19990215)38:4<563::AID-ANIE563>3.0.CO;2-3.CrossRef
9.
go back to reference Adluri S, Helling F, Ogata S, Zhang S, Itzkowitz SH, Lloyd KO, Livingston PO: Immunogenicity of synthetic TF-KLH (keyhole limpet hemocyanin) and sTn-KLH conjugates in colorectal carcinoma patients. Cancer Immunol Immunother. 1995, 41: 185-192. 10.1007/BF01521345.PubMedCrossRef Adluri S, Helling F, Ogata S, Zhang S, Itzkowitz SH, Lloyd KO, Livingston PO: Immunogenicity of synthetic TF-KLH (keyhole limpet hemocyanin) and sTn-KLH conjugates in colorectal carcinoma patients. Cancer Immunol Immunother. 1995, 41: 185-192. 10.1007/BF01521345.PubMedCrossRef
12.
go back to reference Van Holde KE, Miller KI: Hemocyanins. Adv Protein Chem. 1995, 47: 1-8. 10.1016/S0065-3233(08)60545-8.PubMedCrossRef Van Holde KE, Miller KI: Hemocyanins. Adv Protein Chem. 1995, 47: 1-8. 10.1016/S0065-3233(08)60545-8.PubMedCrossRef
13.
go back to reference Harris JR, Markl J: Keyhole limpet hemocyanin (KLH): a biomedical review. Micron. 1999, 30: 597-623. 10.1016/S0968-4328(99)00036-0.PubMedCrossRef Harris JR, Markl J: Keyhole limpet hemocyanin (KLH): a biomedical review. Micron. 1999, 30: 597-623. 10.1016/S0968-4328(99)00036-0.PubMedCrossRef
14.
go back to reference Markl J, Lieb B, Gebauer W, Altenhein B, Meissner U, Harris JR: Marine tumor vaccine carriers: structure of the molluscan hemocyanins KLH and HtH. J Cancer Res Clin Oncol. 2001, 127: R3-R9. 10.1007/BF01470992.PubMedCrossRef Markl J, Lieb B, Gebauer W, Altenhein B, Meissner U, Harris JR: Marine tumor vaccine carriers: structure of the molluscan hemocyanins KLH and HtH. J Cancer Res Clin Oncol. 2001, 127: R3-R9. 10.1007/BF01470992.PubMedCrossRef
15.
go back to reference Rizvi I, Riggs DR, Jackson BJ, McFadden DW: Keyhole limpet hemocyanin: an effective adjunct against melanoma in vivo. Am J Surg. 2007, 194: 628-632. 10.1016/j.amjsurg.2007.08.005.PubMedCrossRef Rizvi I, Riggs DR, Jackson BJ, McFadden DW: Keyhole limpet hemocyanin: an effective adjunct against melanoma in vivo. Am J Surg. 2007, 194: 628-632. 10.1016/j.amjsurg.2007.08.005.PubMedCrossRef
16.
go back to reference Arancibia S, Campo M, Nova E, Salazar F, Becker M: Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non-specific immunostimulatory effects. Eur J Immunol. 2012, 42: 688-699. 10.1002/eji.201142011.PubMedCrossRef Arancibia S, Campo M, Nova E, Salazar F, Becker M: Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non-specific immunostimulatory effects. Eur J Immunol. 2012, 42: 688-699. 10.1002/eji.201142011.PubMedCrossRef
17.
go back to reference Tchorbanov A, Idakieva K, Mihaylova N, Doumanova L: Modulation of the immune response using Rapana thomasiana hemocyanin. Int Immunopharmacol. 2008, 8: 1033-1038. 10.1016/j.intimp.2008.03.008.PubMedCrossRef Tchorbanov A, Idakieva K, Mihaylova N, Doumanova L: Modulation of the immune response using Rapana thomasiana hemocyanin. Int Immunopharmacol. 2008, 8: 1033-1038. 10.1016/j.intimp.2008.03.008.PubMedCrossRef
18.
go back to reference Gesheva V, Idakieva K, Kerekov N, Nikolova K, Mihaylova N, Doumanova L, Tchorbanov A: Marine gastropod hemocyanins as adjuvants of non-conjugated bacterial and viral proteins. Fish Shellfish Immunol. 2011, 30: 135-142. 10.1016/j.fsi.2010.09.018.PubMedCrossRef Gesheva V, Idakieva K, Kerekov N, Nikolova K, Mihaylova N, Doumanova L, Tchorbanov A: Marine gastropod hemocyanins as adjuvants of non-conjugated bacterial and viral proteins. Fish Shellfish Immunol. 2011, 30: 135-142. 10.1016/j.fsi.2010.09.018.PubMedCrossRef
19.
go back to reference Preaux G, Gielens C: Hemocyanins. Cooper Proteins and cooper enzymes. Edited by: Lontie R. 1984, CRC Press, Boca Raton, 159-205. Preaux G, Gielens C: Hemocyanins. Cooper Proteins and cooper enzymes. Edited by: Lontie R. 1984, CRC Press, Boca Raton, 159-205.
20.
go back to reference Corbett TH, Griswold DP, Roberts BJ, Peckham JC, Schabel FM: Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res. 1975, 35: 2434-2439.PubMed Corbett TH, Griswold DP, Roberts BJ, Peckham JC, Schabel FM: Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res. 1975, 35: 2434-2439.PubMed
21.
go back to reference Cheng K, Koeck P, Elmund H, Idakieva K, Parvanova K, Schwarz H, Ternstr m T, Hebert H:Rapana thomasiana hemocyanin (RtH): comparison of the two isoforms, RtH1 and RtH2, at 19 and 16 resolution. Micron. 2006, 37: 566-576. 10.1016/j.micron.2005.11.014.PubMedCrossRef Cheng K, Koeck P, Elmund H, Idakieva K, Parvanova K, Schwarz H, Ternstr m T, Hebert H:Rapana thomasiana hemocyanin (RtH): comparison of the two isoforms, RtH1 and RtH2, at 19 and 16 resolution. Micron. 2006, 37: 566-576. 10.1016/j.micron.2005.11.014.PubMedCrossRef
22.
go back to reference Perbandt M, Guth hrlein E, Rypniewski W, Idakieva K, Stoeva S, Voelter W, Genov N, Betzel C: The structure of a functional unit from the wall of a Gastropod hemocyanin offers a possible mechanism for cooperativity. Biochemistry. 2003, 42: 6341-6346. 10.1021/bi020672x.PubMedCrossRef Perbandt M, Guth hrlein E, Rypniewski W, Idakieva K, Stoeva S, Voelter W, Genov N, Betzel C: The structure of a functional unit from the wall of a Gastropod hemocyanin offers a possible mechanism for cooperativity. Biochemistry. 2003, 42: 6341-6346. 10.1021/bi020672x.PubMedCrossRef
23.
go back to reference Idakieva K, Stoeva S, Voelter W, Gielens C: Glycosylation of Rapana thomasiana Hemocyanin. Comparison with Other Prosobranch (Gastropod) Hemocyanins. Comp Biochem Physiol. 2004, 138B: 221-228. 10.1016/j.cbpc.2004.02.017.CrossRef Idakieva K, Stoeva S, Voelter W, Gielens C: Glycosylation of Rapana thomasiana Hemocyanin. Comparison with Other Prosobranch (Gastropod) Hemocyanins. Comp Biochem Physiol. 2004, 138B: 221-228. 10.1016/j.cbpc.2004.02.017.CrossRef
24.
go back to reference Livingston PO, Zhang S, Lloyd K: Carbohydrate vaccines that induce antibodies against cancer. 1. Rationale. Cancer Immunol Immunother. 1997, 45: 1-9. 10.1007/s002620050394.PubMedCrossRef Livingston PO, Zhang S, Lloyd K: Carbohydrate vaccines that induce antibodies against cancer. 1. Rationale. Cancer Immunol Immunother. 1997, 45: 1-9. 10.1007/s002620050394.PubMedCrossRef
25.
go back to reference Wirguin I, Suturkova Milosevic L, Briani C, Latov N: Keyhole limpet hemocyanin contains Gal (b 1 3)-GalNAc determinants that are cross-reactive with the T antigen. Cancer Immunol Immunother. 1995, 40: 307-310.PubMed Wirguin I, Suturkova Milosevic L, Briani C, Latov N: Keyhole limpet hemocyanin contains Gal (b 1 3)-GalNAc determinants that are cross-reactive with the T antigen. Cancer Immunol Immunother. 1995, 40: 307-310.PubMed
26.
go back to reference Aulino P, Berardi E, Cardillo VM, Rizzuto E, Perniconi B, Ramina C, Padula F, Spugnini EP, Baldi A, Faiola F, Adamo S, Coletti D: Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse. Cancer. 2010, 10: 1-15. Aulino P, Berardi E, Cardillo VM, Rizzuto E, Perniconi B, Ramina C, Padula F, Spugnini EP, Baldi A, Faiola F, Adamo S, Coletti D: Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse. Cancer. 2010, 10: 1-15.
27.
go back to reference Riggs DR, Jackson B, Vona-Davis L, McFadden D: In Vitro Anticancer Effects of a Novel Immunostimulant: Keyhole Limpet Hemocyanin. J Surg Res. 2002, 108: 279-284. 10.1006/jsre.2002.6548.PubMedCrossRef Riggs DR, Jackson B, Vona-Davis L, McFadden D: In Vitro Anticancer Effects of a Novel Immunostimulant: Keyhole Limpet Hemocyanin. J Surg Res. 2002, 108: 279-284. 10.1006/jsre.2002.6548.PubMedCrossRef
28.
go back to reference McFadden DW, Riggs DR, Jackson BJ, Vona-Davis L: Keyhole limpet hemocyanin, a novel immune stimulant with promising anticancer activity in Barrett s esophageal adenocarcinoma. Am J Surg. 2003, 186: 552-555. 10.1016/j.amjsurg.2003.08.002.PubMedCrossRef McFadden DW, Riggs DR, Jackson BJ, Vona-Davis L: Keyhole limpet hemocyanin, a novel immune stimulant with promising anticancer activity in Barrett s esophageal adenocarcinoma. Am J Surg. 2003, 186: 552-555. 10.1016/j.amjsurg.2003.08.002.PubMedCrossRef
29.
go back to reference Idakieva K, Severov S, Svendsen I, Genov N, Stoeva S, Beltramini M, Tognon G, Di Muro P, Salvato B: Structural properties of Rapana thomasiana hemocyanin: isolation, characterization and N-terminal amino acid sequence of two different dissociation products. Comp Biochem Physiol. 1993, 106B: 53-59. Idakieva K, Severov S, Svendsen I, Genov N, Stoeva S, Beltramini M, Tognon G, Di Muro P, Salvato B: Structural properties of Rapana thomasiana hemocyanin: isolation, characterization and N-terminal amino acid sequence of two different dissociation products. Comp Biochem Physiol. 1993, 106B: 53-59.
30.
go back to reference Heirwegh K, Borginon H, Lontie R: Separation and absorption spectra of α-and β-haemocyanin of Helix pomatia. Biochim Biophys Acta. 1961, 48: 517-526. 10.1016/0006-3002(61)90049-X.PubMedCrossRef Heirwegh K, Borginon H, Lontie R: Separation and absorption spectra of α-and β-haemocyanin of Helix pomatia. Biochim Biophys Acta. 1961, 48: 517-526. 10.1016/0006-3002(61)90049-X.PubMedCrossRef
31.
go back to reference Gielens C, Verschueren LJ, Preґaux G, Lontie R: Gel chromatographic separation of the haemocyanins of Helix pomatia. Further electrophoretic and immunological characterization of the components. Comp Biochem Physiol. 1981, 69B: 455-462. Gielens C, Verschueren LJ, Preґaux G, Lontie R: Gel chromatographic separation of the haemocyanins of Helix pomatia. Further electrophoretic and immunological characterization of the components. Comp Biochem Physiol. 1981, 69B: 455-462.
32.
go back to reference Idakieva K, Schwartz H, Genov N, Voelter W, Stoeva S: Rapana thomasiana hemocyanin (RtH): Dissociation and reassociation behaviour of two isoforms. RtH1 and RtH2. Micron. 2002, 33: 7-14. 10.1016/S0968-4328(00)00099-8.PubMedCrossRef Idakieva K, Schwartz H, Genov N, Voelter W, Stoeva S: Rapana thomasiana hemocyanin (RtH): Dissociation and reassociation behaviour of two isoforms. RtH1 and RtH2. Micron. 2002, 33: 7-14. 10.1016/S0968-4328(00)00099-8.PubMedCrossRef
33.
go back to reference Wood EJ, Chaplin MF, Gielens C, De Sadeleer J, Preaux G, Lontie R: Relative molecular mass of the polypeptide chain of βc-haemocyanin of Helix pomatia and carbohydrate composition of the functional units. Comp Biochem Physiol B. 1985, 82: 179-186. 10.1016/0300-9629(85)90723-6.CrossRef Wood EJ, Chaplin MF, Gielens C, De Sadeleer J, Preaux G, Lontie R: Relative molecular mass of the polypeptide chain of βc-haemocyanin of Helix pomatia and carbohydrate composition of the functional units. Comp Biochem Physiol B. 1985, 82: 179-186. 10.1016/0300-9629(85)90723-6.CrossRef
Metadata
Title
Anti-cancer properties of gastropodan hemocyanins in murine model of colon carcinoma
Authors
Vera Gesheva
Stela Chausheva
Nikolina Mihaylova
Iliyan Manoylov
Lyuba Doumanova
Krassimira Idakieva
Andrey Tchorbanov
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2014
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-014-0034-3

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