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PMID: 

Cancer Prev Res (Phila). 2009 Nov ;2(11):975-83. Epub 2009 Oct 27. PMID: 19861543

Abstract Title: 

Effect of orally administered bovine lactoferrin on the growth of adenomatous colorectal polyps in a randomized, placebo-controlled clinical trial.

Abstract: 

Lactoferrin (LF), a secreted, iron binding glycoprotein originally discovered as a component of milk, is found in a variety of exocrine secretions and in the secondary granules of polymorphonuclear leukocytes. Animal experiments have shown that oral administration of bovine lactoferrin (bLF) exerts anticarcinogenesis effects in the colon and other organs of the rat. The aim of this study was to determine whether oral bLF could inhibit the growth of adenomatous colorectal polyps in human patients. A randomized, double-blind, controlled trial was conducted in 104 participants, ages 40 to 75 years, with polyps

PMID: 

Biochim Biophys Acta. 2006 Oct ;1760(10):1536-44. Epub 2006 Jul 7. PMID: 16905260

Abstract Title: 

Antiproliferative and apoptosis inducing effect of lactoferrin and black tea polyphenol combination on hamster buccal pouch carcinogenesis.

Abstract: 

Combination chemoprevention using tea polyphenols as one of the components has received growing consideration in recent years. The present study was designed to evaluate the antiproliferative and apoptosis inducing effects of bovine lactoferrin (bLF) and black tea polyphenol (Polyphenon-B: P-B) combination on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Topical application of DMBA for 14 weeks induced buccal pouch tumours that showed aberrant expression of cytokeratins, a marker for epithelial carcinomas. This was associated with increased cell proliferation and evasion of apoptosis as revealed by upregulation of proliferating cell nuclear antigen, NF-kappaB, mutant p53, Bcl-2 and downregulation of Bax, Fas and caspase 3 protein expression. Although dietary administration of bLF and Polyphenon-B alone significantly reduced tumour incidence, combined administration of bLF and Polyphenon-B was more effective in inhibiting HBP carcinogenesis by restoring normal cytokeratin expression, inhibiting cell proliferation and inducing apoptosis. These findings suggest that a"designer item"approach will be useful for human oral cancer prevention strategies.

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PMID: 

Jpn J Cancer Res. 1999 Mar ;90(3):262-7. PMID: 10359039

Abstract Title: 

Possible chemopreventive effects of bovine lactoferrin on esophagus and lung carcinogenesis in the rat.

Abstract: 

A milk component, bovine lactoferrin (bLF), previously shown by us to be a strong chemopreventive of colon carcinoma development, was examined for its influence on other organs using a rat multi-organ carcinogenesis model. Male F344 rats, aged 6 weeks, were treated sequentially with diethylnitrosamine (DEN, i.p.), dihydroxy-di-N-propylnitrosamine (DHPN, in drinking water) and N-nitrosomethylbenzylamine (NMBA, s.c.) during the first 8 weeks (DDN treatment), and then bLF was administered in the basal diet, at a dose of 2, 0.2, 0.02 or 0.002%. Other groups were given DDN treatment or bLF alone as controls. All surviving animals were killed at week 41, and major organs were examined histopathologically for neoplastic lesions. In the esophagus, a tendency for reduction in development of papillomas was evident in the bLF-treated animals, along with a significant suppression of relatively large-sized papillomas (more than 50 mm3 volume) at the 0.2% dose (P

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PMID: 

J Cell Biochem. 1999 Sep 1 ;74(3):486-98. PMID: 10412049

Abstract Title: 

Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells.

Abstract: 

Lactoferrin inhibits cell proliferation and suppresses tumor growth in vivo. However, the molecular mechanisms underlying these effects remain unknown. In this in vitro study, we demonstrate that treatment of breast carcinoma cells MDA-MB-231 with human lactoferrin induces growth arrest at the G1 to S transition of the cell cycle. This G1 arrest is associated with a dramatic decrease in the protein levels of Cdk2 and cyclin E correlated with an inhibition of the Cdk2 kinase activity. Cdk4 activity is also significantly decreased in the treated cells and is accompanied by an increased expression of the Cdk inhibitor p21(CIP1). Furthermore, we show that lactoferrin maintains the cell cycle progression regulator retinoblastoma protein pRb in a hypophosphorylated form. Additional experiments with synchronized cells by serum depletion confirm the anti-proliferative activity of human lactoferrin. These effects of lactoferrin occur through a p53-independent mechanism both in MDA-MB-231 cells and other epithelial cell lines such as HBL-100, MCF-7, and HT-29. These findings demonstrate that lactoferrin induces growth arrest by modulating the expression and the activity of key G1 regulatory proteins.

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PMID: 

Biometals. 2010 Jun ;23(3):485-92. Epub 2010 Feb 27. PMID: 20191307

Abstract Title: 

Liposomalization of lactoferrin enhanced its anti-tumoral effects on melanoma cells.

Abstract: 

A number of studies have reported the anti-tumoral activity of lactoferrin, a property mediated by a variety of mechanisms such as inhibitory effects on tumor cell growth, NK cell activation, and enhancement of apoptosis. Liposomes are known to be an efficient drug delivery system which can enhance the therapeutic potential of the encapsulated compounds. We have used positively charged liposomes composed of phosphatidylcholine (PC), dioleoylphosphatidylethanolamine (DOPE), cholesterol (Chol) and stearylamine (SA) (6:1:2:1 M ratio) as a carrier system for bovine iron-free Lf (ApoBLf), and compared the in vitro effect of free and liposome-entrapped ApoBLf on the growth and morphology of murine melanoma B16-F10 cells. Liposomal formulation of ApoBLf was found to enhance the capacity of the protein to inhibit the cell proliferation by affecting cell cycle progression. The effect appeared to be due to the capacity of liposomes to increase the uptake of the protein and its accumulation into cells and probably to protect it from degradation, as revealed by fluorescence microscopy and flow cytometry. Our results demonstrate the ability of liposomes to improve the anti-tumor activity of Lf and suggest that liposomal protein may have a potential therapeutic use in the prevention and/or treatment of cancer diseases.

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PMID: 

J Pept Sci. 2014 Oct ;20(10):803-10. Epub 2014 Jun 26. PMID: 24965354

Abstract Title: 

The effect of LfcinB9 on human ovarian cancer cell SK-OV-3 is mediated by inducing apoptosis.

Abstract: 

LfcinB9 is a peptide derived from lactoferricin B. In the present study, the effect and relative mechanism of LfcinB9 on human ovarian cancer cell line (SK-OV-3) in vitro and in vivo was investigated. The data obtained indicated that LfcinB9 exhibited low hemolysis activity and significantly inhibited the proliferation of SK-OV-3 cells in vitro. In addition, the apoptosis of SK-OV-3 cells was induced through up-regulating the production of reactive oxygen species and activating caspase-3, caspase-9 on both transcription and translation level. Finally, LfcinB9 significantly prevented the tumor growth in the SK-OV-3-bearing mice model. These results indicated that LfcinB9 could be a potential agent for the treatment of ovarian cancer.

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PMID: 

J Vet Med Sci. 2008 May ;70(5):443-8. PMID: 18525164

Abstract Title: 

The antiproliferative effect of bovine lactoferrin on canine mammary gland tumor cells.

Abstract: 

Lactoferrin has several biological activities, including antitumor activities in some human and animal tumor cells. Clinical trials have been carried out in human medicine based on these effects. However, the antitumor effects of lactoferrin in veterinary medicine remain unknown. In this in vitro study, we demonstrated that co-incubation of canine mammary gland tumor cells (CIPp and CHMp) and bovine lactoferrin induced growth arrest of tumor cells. This growth arrest was associated with induction of G1 arrest. Furthermore, this effect was stronger in tumor cells than in normal cells. These findings demonstrate that bovine lactoferrin has anti-tumor activity in canine mammary tumors and has the potential for use in tumor-bearing dogs.

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PMID: 

Gan To Kagaku Ryoho. 1998 Aug ;25(10):1557-63. PMID: 9725049

Abstract Title: 

[Antitumor effect of human lactoferrin against newly established human pancreatic cancer cell line SPA].

Abstract: 

This paper describes the antitumor effect of human lactoferrin against the human pancreatic cancer cell line SPA, which was newly established in our laboratory from a metastatic liver tumor of pancreatic origin. In tissue culture, the cancer cells proliferated rapidly at 16 hours of doubling time, and produced tumor markers into the culture medium at a high concentration. Subcutaneous and intraperitoneal transplantation of these neoplastic cells into nude mice resulted in tumor formation and carcinomatous peritonitis. The inhibitory effect of human lactoferrin on the cell growth of SPA was found both in vivo and in vitro. There was significant inhibition of cell growth in vivo at the concentration of 1 microgram/ml of hLf in the culture medium. And in the in vivo assay, hLf delayed the growth of subcutaneously transplanted tumors into BALB/c nude mice, and the effect was retained for two weeks. These results indicate the possibility that hLf will become one of the new drugs for adjuvant therapy against pancreatic cancer.

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PMID: 

J Innate Immun. 2012 ;4(4):387-98. Epub 2012 Mar 16. PMID: 22433582

Abstract Title: 

Inhibition of Epstein-Barr virus infection by lactoferrin.

Abstract: 

Lactoferrin (LF) is a multifunctional glycoprotein that plays an important role in native immune defense against infections, including human herpetic viruses, such as cytomegalovirus and herpes simplex virus types 1 and 2. However, its anti-Epstein-Barr virus (EBV, aγ-herpesvirus) function has not been reported in the literature. EBV is widespread in all human populations and is believed to be linked to tumorigenesis, such as lymphomas and nasopharyngeal carcinoma (NPC). We previously reported that LF expressed a significantly lower level in NPC tissues and was a likely tumor suppressor. Since EBV infection is a major carcinogen of NPC development, we investigated the effect of LF on EBV infection and found that LF could protect human primary B lymphocytes and nasopharyngeal epithelial cells from EBV infection, but had no effect on EBV genome DNA replication. LF prevented EBV infection of primary B cells mediated by its direct binding to the EBV receptor (CD21) on the B-cell surface. Tissue array immunohistochemistry revealed that LF expression was significantly downregulated in NPC specimens, in which high EBV viral capsid antigen-IgA levels wereobserved. These data suggest that LF may inhibit EBV infection and that its downregulation could contribute to NPC development.

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PMID: 

Anticancer Res. 2011 Feb ;31(2):529-34. PMID: 21378334

Abstract Title: 

Binding of lactoferrin to IGBP1 triggers apoptosis in a lung adenocarcinoma cell line.

Abstract: 

BACKGROUND: Lactoferrin (Lf), an iron-binding protein present in mammalian secretions, plays important roles in cancer prevention by inducing apoptosis.MATERIALS AND METHODS: PC-14 lung adenocarcinoma cells were exposed to bovine Lf (bLf) protein and the expression of caspase-3 and apoptosis protease-activating factor-1 (APAF-1) was assessed. To investigate the molecular mechanism of apoptosis induced by bLf, a major Lf-binding protein was screened using a protein microarray with bLf protein as the probe. Protein interaction was demonstrated by co-immunoprecipitation, immunofluorescence and phosphatase activity assay.RESULTS: Lf directly suppressed the proliferation of the PC-14 cells by triggering their apoptosis. Lf was shown to bind specifically with a 36-kDa protein, immunoglobulin (CD79A)-binding protein 1 (IGBP1). The binding complex interacted with the catalytic subunit of protein phosphatase 2A (PP2A), thus reducing the phosphatase activity of PP2A and triggering apoptosis.CONCLUSION: Lf binds IGBP1 and promotes the acceleration of cellular apoptosis.

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