PMID: 

Nanomedicine (Lond). 2018 08 ;13(16):2015-2035. Epub 2018 Sep 7. PMID: 30191764

Abstract Title: 

Inhalable lactoferrin-chondroitin nanocomposites for combined delivery of doxorubicin and ellagic acid to lung carcinoma.

Abstract: 

AIM: The use of inhalable nanomedicines can overcome the Enhanced permeation and retention effect (EPR)-associated drawbacks in lung cancer therapy via systemic nanomedicines.METHODS: We developed a lactoferrin-chondroitin sulfate nanocomplex for the co-delivery of doxorubicin and ellagic acid nanocrystals to lung cancer cells. Then, the nanocomplex was converted into inhalable nanocomposites via spray drying.RESULTS: The resulting 192.3 nm nanocomplex exhibited a sequential faster release of ellagic acid, followed by doxorubicin. Furthermore, the nanocomplex demonstrated superior cytotoxicity and internalization into A549 lung cancer cells mediated via Tf and CD44 receptors. The inhalable nanocomposites exhibited deep lung deposition (89.58% fine particle fraction [FPF]) with powerful antitumor efficacy in lung cancer bearing mice.CONCLUSION: Overall, inhalable lactoferrin-chondroitin sulfate nanocomposites would be a promising carrier for targeted drug delivery to lung cancer.

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PMID: 

Oncotarget. 2016 09 20 ;7(38):62144-62158. PMID: 27556694

Abstract Title: 

Lactoferrin selectively triggers apoptosis in highly metastatic breast cancer cells through inhibition of plasmalemmal V-H+-ATPase.

Abstract: 

Breast cancer is the most common type of cancer affecting women. Despite the good prognosis when detected early, significant challenges remain in the treatment of metastatic breast cancer. The recruitment of the vacuolar H+-ATPase (V-H+-ATPase) to the plasma membrane, where it mediates the acidification of the tumor microenvironment (TME), is a recognized feature involved in the acquisition of a metastatic phenotype in breast cancer. Therefore, inhibitors of this pump have emerged as promising anticancer drugs. Lactoferrin (Lf) is a natural pro-apoptotic iron-binding glycoprotein with strong anticancer activity whose mechanism of action is not fully understood. Here, we show that bovine Lf (bLf) preferentially induces apoptosis in the highly metastatic breast cancer cell lines Hs 578T and MDA-MB-231, which display a prominent localisation of V-H+-ATPase at the plasma membrane, but not in the lowly metastatic T-47D or in the non-tumorigenic MCF-10-2A cell lines. We also demonstrate that bLf decreases the extracellular acidification rate and causes intracellular acidification in metastatic breast cancer cells and, much like the well-known proton pump inhibitors concanamycin A and bafilomycin A1, inhibits V-H+-ATPase in sub-cellular fractions. These data further support that bLf targets V-H+-ATPase and explain the selectivity of bLf for cancer cells, especially for highly metastatic breast cancer cells. Altogether, our results pave the way for more rational in vivo studies aiming to explore this natural non-toxic compound for metastatic breast cancer therapy.

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PMID: 

Protein Pept Lett. 2013 Apr ;20(4):450-8. PMID: 23016584

Abstract Title: 

Immunomodulatory lactoferrin in the regulation of apoptosis modulatory proteins in cancer.

Abstract: 

Lactoferrin (Lf), an iron binding ~80 kDa glycoprotein is a well characterized multifunctional protein found to be present in mammalian milk and in most exocrine secretions. Besides Lf's important physiological roles in the process of iron homeostasis, iron transportation and sequestration, it is well known for its properties such as anti-microbial, antiviral anti-inflammatory and immunomodulatory functions. In the recent decade, Lf has gained significant attention for its future potential use as a safer natural food (bovine milk) derived anti-cancer therapeutic. With regards to Lf's chemopreventive effects in targeting carcinogenesis, both animal and human studies have widely reported its immunomodulatory properties to play a significant role. The deregulation of apoptosis (programmed cell death) mechanisms has not only major implications for the development of uncontrolled tumour growth but evasion of apoptosis is also an important factor affecting drug resistance and radioresistance in cancer. With the exception of few studies, the molecular basis by Lf treatment remains unclear. In this review, by addressing the main features of Lf's structure and function we discuss the recent developments in delineating the therapeutic mechanisms of Lf and its effects on the proteins and receptors modulating apoptosis.

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PMID: 

Biochem Cell Biol. 2017 02 ;95(1):99-109. Epub 2016 Nov 30. PMID: 28169560

Abstract Title: 

Bovine lactoferrin and lactoferricin exert antitumor activities on human colorectal cancer cells (HT-29) by activating various signaling pathways.

Abstract: 

Lactoferrin (Lf) is an iron-binding glycoprotein that is present at high concentrations in milk. Bovine lactoferricin (LfcinB) is a peptide fragment generated by pepsin proteolysis of bovine lactoferrin (bLf). LfcinB consists of amino acid residues 17-41 proximal to the N-terminus of bLf and a disulfide bond between residues 19 and 36, forming a loop. Both bLf and LfcinB have been demonstrated to have antitumor activities. Colorectal cancer is the second most common cause of cancer death in developed countries. We hypothesized that bLf and LfcinB exert antitumor activities on colon cancer cells (HT-29) by triggering various signaling pathways. bLf and LfcinB significantly induced apoptosis in HT-29 cells but not in normal human intestinal epithelial cells, as revealed by the ApoTox-Glo Triplex Assay. The LIVE/DEAD cell viability assay showed that both bLf and LfcinB reduced the viability of HT-29 cells. Transcriptome analysis indicated that bLf, cyclic LfcinB, and linear LfcinB exerted antitumor activities by differentially activating diverse signaling pathways, including p53, apoptosis, and angiopoietin signaling. Immunoblotting results confirmed that both bLf and LfcinBs increased expression of caspase-8, p53, and p21, critical proteins in tumor suppression. These results provide valuable information regarding bLf and LfcinB for potential clinical applications in colon cancer therapy.

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PMID: 

Exp Oncol. 2018 Oct ;40(3):184-189. PMID: 30285009

Abstract Title: 

Effects of exogenous lactoferrin on phenotypic profile and invasiveness of human prostate cancer cells (DU145 and LNCaP) in vitro.

Abstract: 

AIM: To investigate the biological effects of exogenous lactoferrin (LF) on phenotypic profile and invasiveness of human prostate cancer (PC) cells in vitro.MATERIALS AND METHODS: Human PC cell lines (LNCaP, DU-145) were cultured with an exogenous LF at a dose corresponding to IC30. The expression levels of steroid hormone receptors (androgen receptor, estrogen receptor, progesterone receptor), Her2/neu, Ki-67, E- and N-cadherin, were monitored by immunohistochemical analysis. The levels of miRNAs were assessed using q-PCR. The invasive activity of the cells was examined in a standard invasion test.RESULTS: Exogenous LF reduced expression of steroid hormone receptors (ERα and PR) and Ki-67 in both PC cell lines. The expression of E-cadherin increased significantly in LF-treated DU-145 cells. Also, we established the decrease in invasive activity upon LF treatment by 40% and 30% in DU-145 and LNCaP cells, respectively. In DU-145 cells, incubation with exogenousLF resulted in an increase in the expression of oncosuppressive (miR-133a and miR-200b) miRNAs.CONCLUSIONS: Exogenous LF causes the changes in phenotypic characteristics of PC cells and levels of oncogenic and oncosuppressive miRNAs involved in the regulation of key cellular processes.

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PMID: 

Oral Dis. 2019 Apr ;25(3):652-669. Epub 2018 Jun 7. PMID: 29656422

Abstract Title: 

Role of lactoferrin and lactoferrin-derived peptides in oral and maxillofacial diseases.

Abstract: 

The oral cavity harbors different taxonomic groups, the evolutionary coexistence of which develops the oral ecosystem. These resident microorganisms can alter the balance between the physiologic and pathologic conditions that affect the host, both locally and systemically. This highly sophisticated nature of the oral cavity poses a significant therapeutic challenge. Numerous human and animal studies have been conducted to potentiate the efficacy and competence of current treatments of pathologic conditions as well as to develop novel therapeutic modalities. One of these studies is the use of the potent antimicrobial agent lactoferrin (LF), which was originally derived from the host immune system. LF is an 80-kDa glycoprotein that has a free iron sequestration mechanism with evident antimicrobial, anti-tumor, and immunomodulatory properties. A wide range of active peptides have been isolated from the N-terminal region of LF, which possess antimicrobial activities. In this review, we discuss the role of LF and LF-derived peptides under a heterogeneous group of oral and maxillofacial conditions, including bacterial, fungal, viral infections; head and neck cancers; xerostomia; and implantology-bone-related manifestations.

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PMID: 

Curr Pharm Des. 2018 ;24(10):1067-1078. PMID: 29589540

Abstract Title: 

Lactoferrin and Peptide-derivatives: Antimicrobial Agents with Potential Use in Nonspecific Immunity Modulation.

Abstract: 

Lactoferrin (Lf) is a conserved cationic non-heme glycoprotein that is part of the innate immune defense system of mammals. Lf is present in colostrum, milk and mucosal sites, and it is also produced by polymorphonuclear neutrophils and secreted at infection sites. Lf and Lf N-terminus peptide-derivatives named lactoferricins (Lfcins) are molecules with microbiostatic and microbicidal action in a wide array of pathogens. In addition, they display regulatory properties on components of nonspecific immunity, including toll-like receptors, proand anti-inflammatory cytokines, and reactive oxygen species. Mechanisms explaining the ability of Lf and Lfcins to display both up- and down-modulatory properties on cells are not fully understood but result, in part, from their interactions with membrane receptors that elicit biochemical signal pathways, whereas other receptors enable the nuclear translocation of these molecules for the modulation of target genes. The dual role of Lf and Lfcins as antimicrobials and immunomodulators is of biotechnological and pharmaceutical interest. Native Lf and its peptide-derivatives from human and bovine sources, the recombinant versions of the human protein, and their synthetic peptides have potential application as adjunctive agents in therapies to combat infections caused by multi-resistant bacteria and those caused by fungi, protozoa and viruses, as well as in the prevention and reduction of several types of cancer and response to LPS-shock, among other effects. In this review, we summarize the immunomodulatory properties of the unique multifunctional protein Lf and its N-terminus peptides.

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PMID: 

Front Biosci (Schol Ed). 2011 Jun 1 ;3:1080-8. Epub 2011 Jun 1. PMID: 21622257

Abstract Title: 

Lactoferrin and cancer in different cancer models.

Abstract: 

Lactoferrin (Lf) is a multifunctional protein and an essential element of innate immunity. Cancer is a major killer in today's world accounting for around 13% of all deaths according to the World Health Organisation (W.H.O.). The five most common forms of cancer include lung, colorectal, stomach, liver and breast cancer. Lactoferrin is a natural forming iron-binding glycoprotein with antibacterial, antioxidant and anti-carcinogenic effects. It is produced in exocrine glands and is secreted in many external fluids as a first line of defence. Lactoferrin also has the capacity to induce apoptosis and inhibit proliferation in cancer cells as well as restore white and red blood cell levels after chemotherapy. This review focuses on the therapeutic effect bovine sourced lactoferrin has on various forms of cancer in various models. It also focuses on the benefits of 3D in vitro cell culture. 3D cell culture has vast advantages over 2D models including demonstration of realistic therapeutic results and heightened resistance that 2D models fail to display.

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PMID: 

J Dairy Sci. 2011 Jan ;94(1):66-76. PMID: 21183018

Abstract Title: 

The effect of bovine milk lactoferrin on human breast cancer cell lines.

Abstract: 

The evidence that biologically active food components are key environmental factors affecting the incidence of many chronic diseases is overwhelming. However, the full extent of such components in our diet is unknown, as is our understanding of their mechanisms of action. Beyond the interaction of these food components with the gut and intestinal immune functions, whey proteins such as lactoferrin are being tested as anticancer agents. Lactoferrin is an iron-binding protein that has been reported to inhibit several types of cancer. In the present work, the effects of bovine milk lactoferrin on human breast cancer HS578T and T47D cells were studied. The cells were either untreated or treated with lactoferrin concentrations ranging from 0.125 to 125μM. Lactoferrin decreased the cell viability of HS578T and T47D by 47 and 54%, respectively, and increased apoptosis about 2-fold for both cell lines. Proliferation rates decreased by 40.3 and 63.9% for HS578T and T47D, respectively. For the T47D line, cell migration decreased in the presence of the protein. Although the mechanisms of action are not fully known, the results gathered in this work suggest that lactoferrin interferes with some of the most important steps involved in cancer development.

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PMID: 

BMC Immunol. 2012 Jun 18 ;13:32. Epub 2012 Jun 18. PMID: 22708778

Abstract Title: 

Treatment of diabetic mice with undenatured whey protein accelerates the wound healing process by enhancing the expression of MIP-1α, MIP-2, KC, CX3CL1 and TGF-β in wounded tissue.

Abstract: 

BACKGROUND: Continuous diabetes-associated complications are a major source of immune system exhaustion and an increased incidence of infection. Diabetes can cause poor circulation in the feet, increasing the likelihood of ulcers forming when the skin is damaged and slowing the healing of the ulcers. Whey proteins (WPs) enhance immunity during childhood and have a protective effect on some immune disorders. Therefore, in this study, we investigated the effects of camel WP on the healing and closure of diabetic wounds in a streptozotocin (STZ)-induced type I diabetic mouse model.RESULTS: Diabetic mice exhibited delayed wound closure characterized by a significant decrease in an anti-inflammatory cytokine (namely, IL-10) and a prolonged elevation of the levels of inflammatory cytokines (TNF-α, IL-1β and IL-6) in wound tissue. Moreover, aberrant expression of chemokines that regulate wound healing (MIP-1α, MIP-2, KC and CX3CL1) and growth factors (TGF-β) were observed in the wound tissue of diabetic mice compared with control nondiabetic mice. Interestingly, compared with untreateddiabetic mice, supplementation with WP significantly accelerated the closure of diabetic wounds by limiting inflammatory stimuli via the restoration of normal IL-10, TNF-α, IL-1β and IL-6 levels. Most importantly, the supplementation of diabetic mice with WP significantly modulated the expressionof MIP-1α, MIP-2, KC, CX3CL1 and TGF-β in wound tissue compared with untreated diabetic mice.CONCLUSION: Our data demonstrate the benefits of WP supplementation for improving the healing and closure of diabetic wounds and restoring the immune response in diabetic mice.

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