PMID: 

J Agric Food Chem. 2019 Jan 9 ;67(1):140-147. Epub 2018 Nov 27. PMID: 30418775

Abstract Title: 

Effect of Heat Treatment on the Antitumor Activity of Lactoferrin in Human Colon Tumor (HT29) Model.

Abstract: 

To investigate the effect of heat treatment on the antitumor activity of lactoferrin in colon cancer cells and colon tumors, the HT-29 (human intestinal epithelial tumor cell) cell line was exposed to lactoferrin and various heat treatments. The impacts on cell proliferation, invasion, and migration were observed in vitro, and nude mice bearing HT29 tumors were administered lactoferrin and underwent various heat treatments in vivo. In the HT29 cell proliferation test using transwell and scratch analyses, lactoferrin (20 mg/mL) without or with heat treatment (50 and 70°C) significantly inhibited cell proliferation, migration, and invasion (compared with the control, p

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PMID: 

Int J Dev Neurosci. 2015 Apr ;41:28-36. Epub 2014 Dec 8. PMID: 25498991

Abstract Title: 

Lactoferrin induced neuronal differentiation: A boon for brain tumours.

Abstract: 

The cumulative treatments of bovine lactoferrin (bLf) and iron saturated lactoferrin (Fe-bLf) in the neuroblastoma cells showed neuronal differentiating actions evident with the expression of specific differentiating markers,β-tubulin III and neurofilaments. The protein treatments also showed lowered endogenous survivin that is responsible for cell proliferation and the miRNA 584 and miRNA214-3p, required for differentiation. Further, bLf adopted the PI3K signalling predominantly, while Fe-bLf involved both the PI3K and ERK signalling for inducing differentiation. In conclusion, this is the first study to report the neuronal differentiating effects of milk proteins and future studies are warranted for clinical application.

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PMID: 

Int J Biol Macromol. 2017 Feb ;95:232-237. Epub 2016 Nov 15. PMID: 27864056

Abstract Title: 

Lactoferrin nanoparticle mediated targeted delivery of 5-fluorouracil for enhanced therapeutic efficacy.

Abstract: 

Malignant melanoma is an aggressive form of skin cancer with high mortality rates. Common treatments for malignant melanoma involve a combination of radiotherapy and chemotherapy with fluorouracil (5-FU). A major challenge with melanoma treatment is active resistance to chemotherapeutic drugs. Superior treatment outcome lies on balance involving optimum therapeutic doses and the side effects associated with dose escalation. The study aimed to efficiently entrap 5-FU in lactoferrin nanoparticles (LfNPs) in an attempt to enhance its therapeutic efficacy. 5-FU loaded lactoferrin nanoparticles (5-FU-LfNPs) were prepared by sol-oil method with a narrow size distribution of 150±20nm 5-FU-LfNPs exhibits high encapsulation efficiency (64±2.3%) and increased storage stability at 4°C. Competitive ligand binding and lysosomal colocalization studies suggested a receptor mediated uptake for LfNPs internalization in B16F10 cells. Moreover, 5-FU-LfNPs show a pH dependent drug release similar to endosomal pH (pH 5 and 6). In addition compared to free 5-FU, 5-FU- LfNPs showed a higher intracellular uptake, prolonged retention and improved cytotoxicity (2.7-fold) in melanoma cells (B16F10). To conclude, LfNPs represent a superior nano-carrier for the targeted delivery of 5-FU in melanoma cells intended for the efficient treatment of melanoma though detailed in vivo investigations are warranted.

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PMID: 

Exp Oncol. 2018 Oct ;40(3):200-204. PMID: 30284996

Abstract Title: 

Antitumor and genotoxic effects of lactoferrin in Walker-256 tumor-bearing rats.

Abstract: 

AIM: To investigate the influence of exogenous lactoferrin (LF) on tumor growth, energy and lipid metabolism of Walker-256 carcinosarcoma and to assess genotoxic effects of LF.MATERIALS AND METHODS: The study was performed on Walker-256 tumor-bearing rats. Total lipids and phospholipids were determined by thin-layer chromatography. Comet assay was used to investigate the genotoxic effects of LF.RESULTS: Daily i.p. administrations of exogenous LF at concentrations of 1 mg/kg and 10 mg/kg starting from the 4day after tumor transplantation suppressed growth of Walker-256 carcinosarcoma by almost 44%. After treatment with recombinant LF in both doses, the phospholipid composition of Walker-256 carcinosarcoma cells was changed (3-fold increase of phosphatidylethanolamine, 3.4-fold increase of phosphatidylcholine, and 1.8-fold increase of sphingomyelin, while the cardiolipin content decreased by 67%. Exogenous LF was not genotoxic for bone marrow cells (as assessed by the ratio of PCE/NCE, number of micronuclei) and peripheral blood lymphocytes (percentage of DNA in the tail of a comet) in Walker-256 carcinosarcoma-bearing rats.CONCLUSION: Exogenous LF caused the inhibition of Walker-256 carcinosarcoma growth and a decrease in the microviscosity of plasma cell membranes, and exerted no genotoxicity toward bone marrow cells and peripheral blood of experimental animals.

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PMID: 

Biochem Biophys Res Commun. 2018 12 9 ;507(1-4):142-147. Epub 2018 Nov 8. PMID: 30415774

Abstract Title: 

Bovine lactoferrin reverses programming of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition in oral squamous cell carcinoma.

Abstract: 

Epithelial-to-mesenchymal transition (EMT) is a biological process of invasion and metastasis in cancers, including in oral squamous cell carcinoma (OSCC). However, an effective anticancer drug that directly targets EMT has not yet been discovered. Therefore, we aimed to investigate the repressive effects of bovine lactoferrin (bLF) on EMT to achieve mesenchymal-to-epithelial transition (MET) in OSCC. OSCC cell lines, HOC313 (EMT-induced) and SCCVII (without EMT induction), were treated with bLF. The effects of bLF on EMT in OSCC were identified histologically by haematoxylin and eosin staining and observed morphologically and immunohistochemically using an anti-E-cadherin antibody. Expression levels of E-cadherin and vimentin were investigated using RT-PCR and western blotting. Immuno-expression of E-cadherin was examined in vivo in tumour tissues of C3H/HeN mice, transplanted with SCCVII cells, with or without bLF administration. We found that bLF changed the spindle-like mesenchymal cells to cuboidal-like epithelial cells and enhanced the affinity of membrane-bound E-cadherin in HOC313 cells. The transformation ofEMT-MET in HOC313 cells was confirmed by the upregulation of E-cadherin and suppression of vimentin. Moreover, bLF suppressed TWIST expression through downregulation of ERK1/2 phosphorylation. Additionally, the inhibition tumour cell infiltration and increase in E-cadherin expression were observed in xenografts of the mice orally administered with bLF. Thus, based on the results from in vitro and in vivo studies, we concluded that bLF caused the restoration of epithelial properties through MET. Importantly, this finding is novel and is the first report indicating that bLF inhibited EMT and induced MET in OSCC, suggesting that bLF may provide a novel therapeutic strategy in OSCC.

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PMID: 

J Agric Food Chem. 2017 Dec 6 ;65(48):10464-10472. Epub 2017 Nov 20. PMID: 29112400

Abstract Title: 

Lactoferrin Exerts Antitumor Effects by Inhibiting Angiogenesis in a HT29 Human Colon Tumor Model.

Abstract: 

To investigate the effect and potential mechanisms of lactoferrin on colon cancer cells and tumors, HT29 and HCT8 cells were exposed to varying concentrations of lactoferrin, and the impacts on cell proliferation, migration, and invasion were observed. Cell proliferation test showed that high dosage of lactoferrin (5-100 mg/mL) inhibited cell viability in a dose-dependent manner, with the 50% concentration of inhibition at 81.3± 16.7 mg/mL and 101 ± 23.8 mg/mL for HT29 and HCT8 cells, respectively. Interestingly, migration and invasion of the cells were inhibited dramatically by 20 mg/mL lactoferrin, consistent with the significant down regulation of VEGFR2, VEGFA, pPI3K, pAkt, and pErk1/2 proteins. HT29 was chosen as the sensitive cell line to construct a tumor-bearing nude mice model. Notably, HT29 tumor weight was greatly reduced in both the lactoferrin group (26.5 ± 6.7 mg) and the lactoferrin/5-Fu group (14.5 ± 5.1 mg), compared with the control one (39.3 ± 6.5 mg), indicating that lactoferrin functioned as a tumor growth inhibitor. Considering lactoferrin also reduced the growth of blood vessels and the degree of malignancy, we concluded that HT29 tumors were effectively suppressed by lactoferrin, which might be achieved by regulation of phosphorylation from various kinases and activation of the VEGFR2-PI3K/Akt-Erk1/2 pathway.

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PMID: 

Biometals. 2010 Jun ;23(3):399-409. Epub 2010 Apr 21. PMID: 20407806

Abstract Title: 

Cancer prevention by bovine lactoferrin: from animal studies to human trial.

Abstract: 

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and, despite improved colonoscopic screening, CRC is a leading cause of death from cancer. Administration of bovine lactoferrin (bLF) suppresses carcinogenesis in the colon and other organs of test animals, and recently it was shown that ingestion of bLF inhibits the growth of adenomatous polyps in human patients. Here we review work which established bLF as an anti-carcinogenic agent in laboratory animals and the results of a clinical trial which demonstrated that bLF can reduce the risk of colon carcinogenesis in humans.

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PMID: 

Exp Oncol. 2017 Jul ;39(2):106-111. PMID: 29483488

Abstract Title: 

Influence of exogenous lactoferrin on the oxidant/antioxidant balance and molecular profile of hormone receptor-positive and -negative human breast cancer cells in vitro.

Abstract: 

AIM: To investigate the mechanisms of cytotoxic activity and pro-/antioxidant effect of lactoferrin on hormone receptor-positive and receptor-negative breast cancer cells in vitro.MATERIALS AND METHODS: The study was performed on receptor-positive (MCF-7, T47D) and receptor-negative (MDA-MB-231, MDA-MB-468) human breast cancer cell lines. Immunocytochemical staining, flow cytometry, low-temperature electron paramagnetic resonance, and the Comet assay were used.RESULTS: Upon treatment with lactoferrin, the increased levels of reactive oxygen species (ROS) (p

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PMID: 

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2012 Dec ;37(12):1284-9. PMID: 23281388

Abstract Title: 

[New function of lactoferrin: protection against cancer development and metastasis].

Abstract: 

Lactoferrin (LF) is an 80 kD iron-binding glycoprotein that is most highly produced in human and bovine milk and is also widely distributed in mammals. Researches of more than 70 years on lactoferrin prove that the molecule, as a nutritional molecule for mammals, possesses several physiological roles, including maintaining iron absorption, anti-microbial activity and immune modulation. Recent studies have demonstrated that LF can protect against cancer in experimental animals and has anticarcinogenic activity in many human tumors. As a natural nutrition, the"old"gene-lactoferrin has attracted attention from medical community for its"new"anticarcinogenic role.

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PMID: 

PLoS One. 2014 ;9(7):e103298. Epub 2014 Jul 24. PMID: 25057912

Abstract Title: 

Lactoferrin deficiency promotes colitis-associated colorectal dysplasia in mice.

Abstract: 

Nonresolving inflammatory processes affect all stages of carcinogenesis. Lactoferrin, a member of the transferrin family, is involved in the innate immune response and anti-inflammatory, anti-microbial, and anti-tumor activities. We previously found that lactoferrin is significantly down-regulated in specimens of nasopharyngeal carcinoma (NPC) and negatively associated with tumor progression, metastasis, and prognosis of patients with NPC. Additionally, lactoferrin expression levels are decreased in colorectal cancer as compared with normal tissue. Lactoferrin levels are also increased in the various phases of inflammation and dysplasia in an azoxymethane-dextran sulfate sodium (AOM-DSS) model of colitis-associated colon cancer (CAC). We thus hypothesized that the anti-inflammatory function of lactoferrin may contribute to its anti-tumor activity. Here we generated a new Lactoferrin knockout mouse model in which the mice are fertile, develop normally, and display no gross morphological abnormalities. We then challenged these mice with chemically induced intestinal inflammation to investigate the role of lactoferrin in inflammation and cancer development. Lactoferrin knockout mice demonstrated a great susceptibility to inflammation-induced colorectal dysplasia, and this characteristic may be related to inhibition of NF-κB and AKT/mTOR signaling as well as regulation of cell apoptosis and proliferation. Our results suggest that the protective roles of lactoferrin in colorectal mucosal immunity and inflammation-related malignant transformation, along with a deficiency in certain components of the innate immune system, may lead to serious consequences under conditions of inflammatory insult.

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