Bovine Lactoferrin and Lactoferricin, a Peptide Derived from Bovine Lactoferrin, Inhibit Tumor Metastasis in Mice

Overview

Journal Jpn J Cancer Res

Specialty Oncology

Date 1997 Feb 1

PMID 9119747

Citations 46

Authors

Y C Yoo

S Watanabe

R Watanabe

K Hata

K Shimazaki

I Azuma

Affiliations

Soon will be listed here.

Abstract

We investigated the effect of a bovine milk protein, lactoferrin (LF-B), and a pepsin-generated peptide of LF-B, lactoferricin (Lfcin-B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo-lactoferrin (apo-LF-B, 1 mg/mouse) and Lfcin-B (0.5 mg/mouse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y-ML25 cells. However, human apolactoferrin (apo-LF-H) and bovine holo-lactoferrin (holo-LF-B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y-ML25 cells. Similarly, the s.c. administration of apo-LF-B as well as Lfcin-B, but not apo-LF-H and holo-LF-B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16-BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor-induced angiogenesis, both apo-LF-B and Lfcin-B inhibited the number of tumor-induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long-term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo-LF-B significantly suppressed the growth of B16-BL6 cells throughout the examination period, whereas Lfcin-B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16-BL6 melanoma cells, multiple administration of both apo-LF-B and Lfcin-B into tumor-bearing mice significantly inhibited lung metastasis produced by B16-BL6 cells, though only apo-LF-B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo-LF-B and Lfcin-B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of LF-B on tumor metastasis may be related to iron (Fe3+)-saturation.

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References

Yoo Y, Saiki I, Sato K, Azuma I . MDP-Lys(L18), a lipophilic derivative of muramyl dipeptide, inhibits the metastasis of haematogenous and non-haematogenous tumours in mice. Vaccine. 1994; 12(2):175-60. DOI: 10.1016/0264-410x(94)90057-4. View

Christensen B, Fink J, MERRIFIELD R, Mauzerall D . Channel-forming properties of cecropins and related model compounds incorporated into planar lipid membranes. Proc Natl Acad Sci U S A. 1988; 85(14):5072-6. PMC: 281690. DOI: 10.1073/pnas.85.14.5072. View

Shimazaki K, Kawano N, Yoo Y . Comparison of bovine, sheep and goat milk lactoferrins in their electrophoretic behavior, conformation, immunochemical properties and lectin reactivity. Comp Biochem Physiol B. 1991; 98(2-3):417-22. DOI: 10.1016/0305-0491(91)90199-n. View

de Sousa M, Breedvelt F, Trentham D, Lum J . Iron, iron-binding proteins and immune system cells. Ann N Y Acad Sci. 1988; 526:310-22. DOI: 10.1111/j.1749-6632.1988.tb55515.x. View

Zagulski T, Lipinski P, Zagulska A, Broniek S, Jarzabek Z . Lactoferrin can protect mice against a lethal dose of Escherichia coli in experimental infection in vivo. Br J Exp Pathol. 1989; 70(6):697-704. PMC: 2040730. View

Bezault J, Bhimani R, Wiprovnick J, Furmanski P . Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Res. 1994; 54(9):2310-2. View

Shau H, Kim A, Golub S . Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin. J Leukoc Biol. 1992; 51(4):343-9. View

Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K, Tomita M . Identification of the bactericidal domain of lactoferrin. Biochim Biophys Acta. 1992; 1121(1-2):130-6. DOI: 10.1016/0167-4838(92)90346-f. View

Hauer J, Voetsch W, Anderer F . Identification of a mannose-acetate-specific 87-kDa receptor responsible for human NK and LAK activity. Immunol Lett. 1994; 42(1-2):7-12. DOI: 10.1016/0165-2478(94)90027-2. View

10.

Tomita M, Takase M, Bellamy W, Shimamura S . A review: the active peptide of lactoferrin. Acta Paediatr Jpn. 1994; 36(5):585-91. DOI: 10.1111/j.1442-200x.1994.tb03250.x. View

11.

Law B, Reiter B . The isolation and bacteriostatic properties of lactoferrin from bovine milk whey. J Dairy Res. 1977; 44(3):595-9. DOI: 10.1017/s0022029900020550. View

12.

Arnold R, Brewer M, Gauthier J . Bactericidal activity of human lactoferrin: sensitivity of a variety of microorganisms. Infect Immun. 1980; 28(3):893-8. PMC: 551035. DOI: 10.1128/iai.28.3.893-898.1980. View

13.

Bellamy W, Takase M, Wakabayashi H, Kawase K, Tomita M . Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. J Appl Bacteriol. 1992; 73(6):472-9. DOI: 10.1111/j.1365-2672.1992.tb05007.x. View

14.

Sawatzki G, Rich I . Lactoferrin stimulates colony stimulating factor production in vitro and in vivo. Blood Cells. 1989; 15(2):371-85. View

15.

Yoo Y, Saiki I, Sato K, Azuma I . B30-MDP, a synthetic muramyl dipeptide derivative for tumour vaccination to enhance antitumour immunity and antimetastatic effect in mice. Vaccine. 1992; 10(11):792-7. DOI: 10.1016/0264-410x(92)90515-l. View

16.

Gahr M, Speer C, Damerau B, Sawatzki G . Influence of lactoferrin on the function of human polymorphonuclear leukocytes and monocytes. J Leukoc Biol. 1991; 49(5):427-33. DOI: 10.1002/jlb.49.5.427. View

17.

Horwitz D, Bakke A, Abo W, Nishiya K . Monocyte and NK cell cytotoxic activity in human adherent cell preparations: discriminating effects of interferon and lactoferrin. J Immunol. 1984; 132(5):2370-4. View

18.

Nishiya K, Horwitz D . Contrasting effects of lactoferrin on human lymphocyte and monocyte natural killer activity and antibody-dependent cell-mediated cytotoxicity. J Immunol. 1982; 129(6):2519-23. View

19.

Saiki I, Sato K, Yoo Y, Murata J, Yoneda J, Kiso M . Inhibition of tumor-induced angiogenesis by the administration of recombinant interferon-gamma followed by a synthetic lipid-A subunit analogue (GLA-60). Int J Cancer. 1992; 51(4):641-5. DOI: 10.1002/ijc.2910510422. View

20.

Montreuil J, TONNELAT J, MULLET S . [Preparation and properties of lactosiderophilin (lactotransferrin) of human milk]. Biochim Biophys Acta. 1960; 45:413-21. DOI: 10.1016/0006-3002(60)91478-5. View