Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice.
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.
Yoo
Y C
YC
Institute of Immunological Science, Faculty of Agriculture, Hokkaido University, Sapporo.
Watanabe
S
S
Watanabe
R
R
Hata
K
K
Shimazaki
K
K
Azuma
I
I
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002417:Cattle; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007781:Lactoferrin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D007940:Leukemia L5178 / Q000517:prevention & control*; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms
D000970:Antineoplastic Agents; C082171:lactoferricin B; D007781:Lactoferrin