lactoferrin and Neoplasms

Lactoferrin (Lf) is secreted by ectodermal tissue and has a structure similar to that of transferrin. Although Lf seems to be multifunctional, its main function is related to the natural defense system of mammals. The present review aims to highlight the major actions of Lf, including the regulation of cell growth, the inhibition of toxic compound formation, the removal of harmful free radicals and its important role in immune response regulation. Moreover, Lf has antibacterial, antiviral, antioxidant, anticancer and anti‑inflammatory activities. In addition, the use of Lf for functionalization of drug nanocarriers, with emphasis on tumor‑targeted drug delivery, is illustrated. Such effects serve as an important theoretical basis for its future development and application. In neurodegenerative diseases and the brains of elderly people, Lf expression is markedly upregulated. Lf may exert an anti‑inflammatory effect by inhibiting the formation of hydroxyl free radicals. Through its antioxidant properties, Lf can prevent DNA damage, thereby preventing tumor formation in the central nervous system. In addition, Lf specifically activates the p53 tumor suppressor gene.

Topics: Adjuvants, Immunologic; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Immunomodulating Agents; Lactoferrin; Nanotechnology; Neoplasms

A successful drug delivery to a specific site relies on two essential factors including; efficient entrapment of the drug within the carrier and successful delivery of drug- loaded nanocarrier to the target site without opsonisation or drug release in the circulation before reaching the organ of interest. Lactoferrin (LF) is a glycoprotein belonging to the transferrin (TF) family which can bind to TF receptors (TFRs) and LF membrane internalization receptors (LFRs) highly expressed on the cell surface of both highly proliferating cancer cells and blood brain barrier (BBB), which in turn can facilitate its accessibility to the cell nucleus. This merit could be exploited to develop actively targeted drug delivery systems that can easily cross the BBB or internalize into tumor cells. In this review, the most recent advances of utilizing LF as an active targeting ligand for different types of nanocarriers including: inorganic nanoparticles, dendrimers, synthetic biodegradable polymers, lipid nanocarriers, natural polymers, and nanoemulstions will be highlighted. Collectively, LF seems to be a promising targeting ligand in the field of nanomedicine.

Topics: Blood-Brain Barrier; Dendrimers; Drug Carriers; Drug Liberation; Humans; Lactoferrin; Liposomes; Magnetite Nanoparticles; Nanomedicine; Nanoparticles; Nanostructures; Neoplasms; Receptors, Transferrin; Transferrin

Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Consensus; Endoscopy; Endoscopy, Digestive System; Enterocolitis; Gastroenterology; Gastrointestinal Diseases; Guidelines as Topic; Humans; Infliximab; Lactoferrin; Leukocyte L1 Antigen Complex; Neoplasms; Patient Care Management; Societies, Medical; Tumor Necrosis Factor-alpha; United Kingdom

Lactoferrin, an iron storage protein, is known for its microbicidal activity and its ability to modulate the immune system, mediated through specific interactions with receptors on cell surfaces for internalization. These activities confer a significant versatility to lactoferrin, presenting it as a targeting ligand to disease-bearing cells. Early efforts in developing targeted delivery systems have focused on nano- and microcomposites comprised of metal and polymeric materials. These can be targeted through conjugation or adsorption of lactoferrin to achieve recognition to receptor-expressing cells. More recently, efforts are underway to utilize lactoferrin itself as a medium in loading the therapeutic agent. The functional efficiency of drug-loaded lactoferrin nanoparticles has been evaluated in different disease conditions such as cancer, HIV, Parkinson's disease, etc. This review will present the details of composition and performance of various delivery systems designed and developed using lactoferrin as targeting agent for the treatment of cancer.

Topics: Drug Delivery Systems; Humans; Iron; Lactoferrin; Nanoparticles; Neoplasms

Cathepsin G (CatG) is involved in controlling numerous processes of the innate and adaptive immune system. These features include the proteolytic activity of CatG and play a pivotal role in alteration of chemokines as well as cytokines, clearance of exogenous and internalized pathogens, platelet activation, apoptosis, and antigen processing. This is in contrast to the capability of CatG acting in a proteolytic-independent manner due to the net charge of arginine residues in the CatG sequence which interferes with bacteria. CatG is a double-edged sword; CatG is also responsible in pathophysiological conditions, such as autoimmunity, chronic pulmonary diseases, HIV infection, tumor progression and metastasis, photo-aged human skin, Papillon-Lefèvre syndrome, and chronic inflammatory pain. Here, we summarize the latest findings for functional responsibilities of CatG in immunity, including bivalent regulation of major histocompatibility complex class I molecules, which underscore an additional novel role of CatG within the immune system.

Topics: Animals; Antigen Presentation; Autoimmunity; Cathepsin G; Gene Expression Regulation; Histocompatibility Antigens Class I; Humans; Killer Cells, Natural; Lactoferrin; Neoplasms; T-Lymphocytes, Regulatory; Virus Diseases

Lactoferrin (Lf), an iron-binding protein from the transferrin family has been reported to have numerous functions. Even though Lf was first isolated from milk, it is also found in most exocrine secretions and in the secondary granules of neutrophils. Antimicrobial and anti-inflammatory activity reports on lactoferrin identified its significance in host defense against infection and extreme inflammation. Anticarcinogenic reports on lactoferrin make this protein even more valuable. This review is focused on the structural configuration of iron-containing and iron-free forms of lactoferrin obtained from different sources such as goat, camel and bovine. Apart for emphasizing on the specific beneficial properties of lactoferrin from each of these sources, the general antimicrobial, immunomodulatory and anticancer activities of lactoferrin are discussed here. Implementation of nanomedicinial strategies that enhance the bioactive function of lactoferrin are also discussed, along with information on lactoferrin in clinical trials.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Camelus; Cattle; Clinical Trials as Topic; Goats; Humans; Immunity, Innate; Inflammation; Iron; Iron Chelating Agents; Lactoferrin; Neoplasms; Neutrophils

Lactoferrin (Lf) is one of the food protein belonged to the innate immune system. Apart from its main biological function of binding and transport of iron ions, lactoferrin also has many other functions and properties such as antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, anti-allergic and radioprotecting. Lf is usually used as additives of food and cosmetics. The research of lactoferrin has been increasingly reported, and the application of lactoferrin as a drug carrier has drawn extensive attention over the recent year. In this paper, researches of lactoferrin as drug carriers are classified and summarized in brain targeting, liver tumor targeting, lung tumor targeting and oral delivery systems according to their different characteristics.

Topics: Administration, Oral; Brain; Drug Carriers; Humans; Lactoferrin; Neoplasms

Lactoferrin has been widely studied over the last 70 years, and its role in diverse biological functions is now well known and generally accepted by the scientific community. Usually, alterations of the lactoferrin gene in cells are associated with an increased incidence of cancer. Several studies suggest that exogenous treatment with lactoferrin and its derivatives can efficiently inhibit the growth of tumors and reduce susceptibility to cancer. None of these studies, however, reported a consistent outcome with regard to the mechanisms underlying the anticancer effects of lactoferrin. In this review, the association of lactoferrin with cancer is thoroughly discussed, from lactoferrin gene expression to the potential use of lactoferrin in cancer therapy. Lactoferrin cytotoxicity against several cancers is reported to occur in distinct ways under different conditions, namely by cell membrane disruption, apoptosis induction, cell cycle arrest, and cell immunoreaction. Based on these mechanisms, new strategies to improve the anticancer effects of the lactoferrin protein and/or its derivatives are proposed. The potential for lactoferrin in the field of cancer research (including as a chemotherapeutic agent in cancer therapy) is also discussed.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Membrane; Cells; Chemoprevention; Gene Expression; Genetic Variation; Humans; Lactoferrin; Neoplasms

This review mainly summarizes results of recent studies on the anticancer activity of the multifunctional protein lactoferrin (Lf) and its derived peptide lactoferricin (Lfcin). The basic information on Lf and Lfcin, such as their sources, structures, and biological properties which favor their antitumor activity is introduced. The major anticancer mechanisms of Lf and Lfcin including cell cycle arrest, apoptosis, anti-angiogenesis, antimetastasis, immune modulation and necrosis are discussed. Other information from in vivo studies employing a mouse model is also provided. In addition, the roles of talatoferrin and delta lactoferrin, as well as improvement in drug delivery will be covered.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Humans; Lactoferrin; Necrosis; Neoplasms; Neovascularization, Pathologic

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.

Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Cattle; Homeostasis; Humans; Immunologic Factors; Iron; Lactoferrin; Neoplasms; Protein Isoforms

Lactoferrin (LF) is an iron-binding glycoprotein of the transferrin family, today known to have multifunctional physiological activities. In humans, under normal conditions, LF has been found in blood, mucosal secretions, gastrointestinal fluids, urine and mostly in milk and colostrum. The first pioneering immunohistochemical report about LF distribution in human tissues dated in 1978; successively, many studies have been performed to analyze the LF immunohistochemical pattern in different normal and neoplastic tissues. In this review, we present data from literature concerning the evidence of LF in tumors together with those by us obtained during more than 25 years; the immunohistochemical applications to human neoplastic tissues have been done to investigate the LF pathogenetic role as well as its activity in cancer. After a systematic analysis of LF immunoreactivity in different human districts, a possible explanation for its presence and function has been modulated for each site or tissue, according to experimental evidences obtained either by in vivo as well as by in vitro studies.

Topics: Humans; Immunohistochemistry; Lactoferrin; Neoplasms; Tissue Distribution

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.

Topics: Administration, Oral; Animals; Apoptosis; Blood Cells; Cattle; Cell Culture Techniques; Cell Proliferation; Dogs; Humans; Immunity, Innate; Lactoferrin; Mice; Models, Biological; Neoplasms; Rats

Lactoferrin (LF) is an iron-binding glycoprotein that is composed of the transferrin family and is predominantly found in the products of the exocrine glands located in the gateways of the digestive, respiratory, and reproductive systems, suggesting a role in the non-specific defence against invading pathogens. Additionally, several physiological roles have been attributed to LF, namely regulation of iron homeostasis, host defence against infection and inflammation, regulation of cellular growth, and differentiation and protection against cancer development and metastasis. These findings have suggested LF's great potential therapeutic use in cancer disease prevention and/or treatment, namely as a chemopreventive agent. This review looks at the recent advances in understanding the mechanisms underlying the multifunctional roles of LF and future perspectives on its potential therapeutic applications.

Topics: Animals; Anticarcinogenic Agents; Chemoprevention; Homeostasis; Humans; Iron; Lactoferrin; Milk, Human; Neoplasms

Until relatively recently, the only significant source of lactoferrin in the diet was human lactoferrin, provided in breast milk. Today, however, bovine lactoferrin, isolated by dairy technology, as well as recombinant human lactoferrin are commercially available and can be added to foods and clinical products with perceived benefits to the consumer. In this review, the potential biological functions of dietary lactoferrin are described and critically examined.. Ingested lactoferrin has been suggested to exert antibacterial and antiviral activities in the intestine, in part through a direct effect on pathogens, but possibly also affecting mucosal immune function. The latter function is most likely mediated by lactoferrin being taken up by cells via a unique receptor-mediated pathway and affecting gene transcription. Lactoferrin has also been shown to enhance iron status of infants and pregnant women, possibly also via the receptor-mediated pathway. In addition, lactoferrin can stimulate intestinal cell proliferation and differentiation, causing expansion of tissue mass and absorptive capacity. On the contrary, lactoferrin has been shown to inhibit carcinogenesis. Recent findings also suggest that oral lactoferrin treatment may have an anti-inflammatory effect on pregnant women, reducing pregnancy complications.. Lactoferrin treatment may have beneficial preventive and therapeutic effects on infection, inflammation, and cancer as well as enhancing iron status and growth in vulnerable groups.

Topics: Anemia, Iron-Deficiency; Animals; Dietary Supplements; Female; Humans; Infant; Infections; Inflammation; Iron; Lactoferrin; Neoplasms; Pregnancy; Pregnancy Complications

Lactoferrin (Lf) is an iron-binding glycoprotein of the transferrin family that is expressed and secreted by glandular cells and found in the secondary granules of neutrophils from which it is released in infected tissues and blood during the inflammatory process. Initially described as an iron-binding molecule with bacteriostatic properties, Lf is now known to be a multifunctional or multi-tasking protein. It is a major component of the innate immune system of mammals. Its protective effects range from direct anti-microbial activities against a large panel of microorganisms including bacteria, viruses, fungi, and parasites, to anti-inflammatory and anti-cancer activities. While iron chelation is central to some of the biological functions of Lf, other activities involve interactions of Lf with molecular and cellular components of both hosts and pathogens. Its powerful antimicrobial activities, immunomodulatory properties and prevention of septic shock, anti-carcinogenic functions and its growing importance in iron delivery and bone growth, combined with the data obtained either by in vivo studies or clinical trials, make this molecule and its derivatives very promising tools for health or nutritional applications.

Topics: Animals; Apoptosis; Blood Bactericidal Activity; Bone Remodeling; Cattle; Humans; Immunity, Innate; Infections; Inflammation; Intestinal Absorption; Iron, Dietary; Lactoferrin; Mammals; Models, Molecular; Neoplasms; Neovascularization, Physiologic; Protein Conformation

A considerable array of diseases are now recognized to be associated with misplacement of iron. Excessive deposits of the metal in sensitive tissue sites can result in formation of destructive hydroxyl radicals as well as in stimulation of growth of neoplastic and microbial cell invaders. To counteract potential iron damage, hosts employ the iron chelators, transferrin and lactoferrin. These proteins have been recently developed into pharmaceutical products. Additionally, a variety of low molecular mass iron chelators are being used/tested to treat whole body iron loading, and specific diseases for which the metal is a known or suspected risk factor.

Topics: Animals; Bacterial Infections; Deferoxamine; Free Radicals; Humans; Iron; Iron Chelating Agents; Iron Overload; Lactoferrin; Mycoses; Neoplasms; Transferrin

Cancer treatment by conventional chemotherapy is hindered by toxic side effects and the frequent development of multi-drug resistance by cancer cells. Cationic antimicrobial peptides (CAPs) are a promising new class of natural-source drugs that may avoid the shortcomings of conventional chemotherapy because certain CAPs exhibit selective cytotoxicity against a broad spectrum of human cancer cells, including neoplastic cells that have acquired a multi-drug-resistant phenotype. Tumour cell killing by CAPs is usually by a cell membrane-lytic effect, although some CAPs can trigger apoptosis in cancer cells via mitochondrial membrane disruption. Furthermore, certain CAPs are potent inhibitors of blood vessel development (angiogenesis) that is associated with tumour progression. This article reviews the mechanisms by which CAPs exert anticancer activity and discusses the potential application of selected CAPs as therapeutic agents for the treatment of human cancers.

Topics: Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides; Antineoplastic Agents; Apoptosis; Cell Membrane; Cell Survival; Defensins; Drug Carriers; Drug Design; Humans; Lactoferrin; Magainins; Mitochondrial Membranes; Molecular Sequence Data; Neoplasms; Protein Structure, Secondary; Proteins; Xenopus Proteins

Lactoferrin, an evolutionarily old protein of the transferrin family, is among the proteins constituting the system of innate immunity; its action, however, also extends to the regulation of acquired immunity and other immunological phenomena. The actions of LF, confirmed in numerous in vitro and in vivo models, include participation in iron homeostasis, immunoregulatory properties, anti-inflammatory, anti-tumor, and analgesic actions, regulation of bone metabolism, participation in embryonic development, reproductive functions, and others. LF plays an important role in the normal development of a newborn. The anti-tumor properties of LF were discovered about a decade ago and have been confirmed in many laboratory, preclinical, and clinical studies. The immunomodulatory properties of LF play a major role in its anti-tumor actions. Such actions of LF appeared particularly effective in cancer patients with impaired immunity. The growth of tumors is facilitated by low expressions of MHC and co-stimulatory antigens on tumor cells and the induction of suppressor cells and other inhibitory products by tumors. Enhancement of an anti-tumor immunological response may, therefore, restrict tumor growth. Studies showed that LF elevates the number and increases the activity of T and B lymphocytes and NK cells, stimulates the release of a number of cytokines (IL-1, -6, -8, -18, IFN-gamma, TNF alpha), increases phagocytic activity and cytotoxicity of monocytes/macrophages, accelerates the maturation of T and B cells, and elevates the expression of several types of cellular receptors, such as CD4, zeta chain of the CD3 complex, LFA-1, CD11, ICAM-1, and selectin P. Apart from its immunomodulatory properties, LF exhibits direct anti-tumor actions, such as lytic, pro-apoptotic, anti-proliferative, anti-angiogenic, anti-oxidant activity and the chelation of iron ions. LF also possesses chemo-preventive properties, regulates the activity of phase I and II enzymes participating in the activation and detoxification of carcinogens, and regulates the composition of the intestinal microflora. In this way it prevents the generation of tumors and their development at early stages of carcinogenesis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Bone and Bones; Chemoprevention; Humans; Immunity, Cellular; Infant, Newborn; Iron; Lactoferrin; Neoplasms

The use of anticancer agents forms an important part for treatment of cancer of various types. Complexes with cis-platinum compounds have been used for the prevention and treatment of cancers. Quite a number of these metal-containing complexes have been isolated, chemically prepared and characterized for the treatment of cancer. Many of these compounds display potent cytotoxic effects, although there is a considerable progress made in the design of novel anticancer agents. Some of these compounds showed strong inhibitory effects on cancer growth with a potential to become anti-cancer drugs. However, the unwanted deleterious effects hamper the common use of these agents as anticancer drugs. Nevertheless, the use of protective agents during, before or after treatment with anti-cancer agents in combination therapy has proven effective in the treatment. The results prompt the study of the biologic activities and the design of better modality for treatment and prevention of cancer. Here, we review the potential and reduction of cytotoxic properties of the prominent member of this class of metal compounds for the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Humans; Lactoferrin; Neoplasms; Organoplatinum Compounds; Patents as Topic

Colostrum and milk are rich in proteins and peptides which play a crucial role in innate immunity when transferred to the offspring and may accelerate maturation of the immune system in neonates. The immunotropic properties of these proteins prompted investigators research their potential application in prevention and therapy. Lactoferrin (LF) exhibits antibacterial, antifungal, antiviral, antiparasitice, and antitumoral activities. It is protective with regard to intestinal epithelium, promotes bone growth, and accelerates the recovery of immune system function in immunocompromised animals. LF was tried in the treatment of hepatitis C infection and the intestinal form of graft-versus-host disease (GvHD). A proline-rich polypeptide (PRP) demonstrated a variety of immunotropic functions, including the promotion of T-cell maturation and inhibition of autoimmune disorders. PRP, in the form of chewable tablets (Colostrinin) was recently found to improve or stabilize the health status of Alzheimer's disease patients. Casein and casein-derived peptides showed protective activities in enamel demineralization and as caries-preventing agents. The protein hydrolyzates were also protective in diabetic animals, reduced tumor growth, had antihypertensive activity and diminished colicky symptoms in infants. Glycomacropeptide (GMP), a peptide derived from kappa-casein, exhibited various antibacterial and antithrombotic activities. Alpha-lactalbumin (LA) demonstrated antiviral, antitumoral and anti-stress properties. LA-enriched diets were anxiolytic, lowered blood pressure in rats, prevented diarrhea, and led to a better weight gain in malnourished children. HAMLET, a complex of LA and oleic acid, was effective in patients with cutaneous papillomas. Lysozyme found application in infant formulas, the treatment of periodentitis, and the prevention of tooth decay. Milk enriched in lysozyme was used in feeding premature infants suffering from concomitant diseases. Interesting, antibacterial properties were exhibited by lactoperoxidase. Both lysozyme and lactoperoxidase required cooperative action with LF in combating bacteria. In conclusion, preparations derived from milk and colostrum are effective, easily bioaccessible, and safe, finding wide application in prevention and therapy for newborns and adults.

Topics: Adult; Alzheimer Disease; Animals; Anti-Infective Agents; Antineoplastic Agents; Autoimmune Diseases; Caseins; Child; Colostrum; Female; Humans; Infant; Infant, Newborn; Intercellular Signaling Peptides and Proteins; Lactoferrin; Lactoperoxidase; Malnutrition; Milk Proteins; Neoplasms; Peptides; Pregnancy; Tooth Diseases

Agennix is developing recombinant human (rh) lactoferrin, a glycoprotein with antibiotic, anti-inflammatory and immunomodulatory activity, for the potential treatment of cancers, asthma and chronic wounds. rh Lactoferrin is currently undergoing phase II clinical trials.

Topics: Aspergillus; Asthma; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Lactoferrin; Neoplasms; Recombinant Proteins; Wound Healing; Wounds and Injuries

This paper reviews our current knowledge of the structure and function of the iron-binding protein lactoferrin. In particular, it attempts to relate the various proposed physiological functions of lactoferrin to its most characteristic biochemical properties, i.e. its ability to bind iron and its highly basic nature. The extent to which various physiological functions can be considered as definitely established is critically reviewed, and suggestions for future research are proposed.

Topics: Animals; Autoantibodies; Bacteria; Gene Expression Regulation; Humans; Inflammation; Iron; Lactoferrin; Neoplasms; Parasites; Viruses

In experimental studies, bovine lactoferrin (bLF) has been found to significantly inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Furthermore, concomitant administration with carcinogens resulted in inhibition of colon carcinogenesis, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2), which is preferentially induced by carcinogenic heterocyclic amines. Enhancement of the activities of their phase II counterparts, such as glutathione S-transferase might have also played a critical role in post-initiation suppression in a study of tongue carcinogenesis. Anti-metastatic effects were moreover detected when bLF was given intragastrically to mice bearing highly metastatic colon carcinoma 26 cells (Co 26Lu), with apparent enhancing influence on local and systemic immunity. Marked increase in the number of cytotoxic T and NK cells in the mucosal layer of the small intestine and peripheral blood cells was thus found, this in turn enhancing the production of Interleukin 18 (IL-18) and caspase-1 in the epithelial cells of the small intestine, with possible consequent induction of interferon (IFN)-gamma positive cells. Furthermore, bLF has been found to exert anti-hepatitis C virus (HCV) activity in a preliminary clinical trial in patients with chronic active hepatitis due to this virus, a main causative factor in hepatocellular carcinoma development in Japanese. More extensive clinical trials are now underway in the National Cancer Center Hospital and other institutes to further explore the preventive potential against colon carcinogenesis.

Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Colonic Neoplasms; Hepatitis C, Chronic; Humans; Immunity, Mucosal; Lactoferrin; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Pilot Projects

Topics: Humans; Immunohistochemistry; Lactoferrin; Neoplasms

Neutrophil influx into tissues occurs in many diverse diseases and can be associated with both beneficial and injurious effects. We hypothesize that the stimulus for certain neutrophilic inflammatory responses can be reduced to a series of competing reactions for iron, with either a labile or reactive coordination site available, between host chelators and chelators not indigenous to that specific living system. The iron focuses the transport of host phagocytic cells through a metal catalyzed generation of oxidant sensitive mediators including cytokines and eicosanoids. Many of these products are chemotactic for neutrophils. We also postulate that the iron increases the activity of the phagocyte associated NADPH oxidoreductase in the neutrophil. The function of this enzyme is likely to be the generation of superoxide in the host's attempt to chemically reduce and dislodge the iron from its chelate complex. After the reoxidation of Fe2+ in an aerobic environment, Fe3+ will be coordinated by host lactoferrin released by the neutrophil. When complexed by this glycoprotein, the metal does not readily undergo oxidation/reduction and is safely transported to the macrophages of the reticuloendothelial system where it is stored in ferritin. Finally, we propose that the neutrophil will attempt to destroy the chelator not indigenous to the host by releasing granular contents other than lactoferrin. Inability to eliminate the chelator allows this sequence to repeat itself, which can lead to tissue injury. Such persistence of a metal chelate in the host may be associated with biomineralization, fibrosis, and cancer.

Topics: Animals; Fibrosis; Free Radicals; Humans; Inflammation; Iron; Iron Chelating Agents; Lactoferrin; NADH, NADPH Oxidoreductases; Neoplasms; Neutrophils; Oxidation-Reduction; Phagocytes

Lactoferrin (LF) is an iron-binding protein found in milk and other secretory fluids of mammals as well as in secondary granules of neutrophils. Receptors for LF were detected and isolated on activated T and B cells, monocytes, intestinal brush border cells, platelets and neoplastic cells. Very low physiologic serum levels of LF increase significantly upon infection. Serum concentration of LF is also elevated in rheumatoid patients. It is suggested that the ability of LF to bind an excess of Fe() ions, needed for growth of microorganisms and tumors, represents an important defence mechanism in humans. LF, in addition, may contribute to the protection against pathogens and their metabolites by enhancing phagocytosis, cell adherence and controlling release of proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha. The protein diminishes also damaging effects of free radical release. LF possesses interesting immunotropic properties with regard to immature T and B cells by promoting phenotypic and functional maturation of these cells. LF also controls the effector phase of cellular immune response and inhibits manifestations of autoimmune response in mice. One molecular form of LF with a ribonuclease activity may have a prognostic value in breast cancer. Lactoferrin may be potentially applied in neutropenic patients or in patients with bleeding disorders as a preoperative immunomodulator.

Topics: Adjuvants, Immunologic; Animals; Cell Adhesion; Cytokines; Humans; Immunity, Cellular; Infections; Lactoferrin; Mice; Neoplasms; Phagocytosis; Receptors, Cell Surface

Lactoferrin is a protein present in many fluids of the human organism and in the secondary granules of polymorphonuclear cells (PMN). In the blood stream lactoferrin favours the segregation of PMN by mediating and amplifying the immune response, and realizes a negative feedback control on the Colony Forming Unit Granulocyte/Macrophage (CFU-GM) proliferation. At intestinal level it promotes iron absorption and prevents bacterial overgrowth. The antibacterial effect of lactoferrin is used clinically to prevent bacterial infections in neutropenic patients submitted to chemotherapy for leukemic diseases type M1, M2, M4 and M5, according to FAB criteria. In patients affected by chronic pancreatitis the lactoferrin concentration, in duodenal juice, is found to be significantly higher than in normal subjects. This finding suggests a pathogenetic role of the protein in chronic pancreatitis.

Topics: Bacteria; Chronic Disease; Granulocytes; Humans; Lactoferrin; Lipid Peroxidation; Neoplasms; Neutrophils; Pancreatitis

Neoplasms are characterized by increased perfusion, increased permeability of their capillary beds to macromolecules, and a delay in new lymphatic vessel growth. These lead to the increased entry and residency time of macromolecules in the interstitial space of tumors. Multiple factors contribute to the localization of 67Ga in tumors. Adequate blood supply is essential; at areas with no blood supply such as the necrotic center of a large tumor, there is no 67Ga accumulation. Gallium-67, mainly in the form of transferrin-67Ga complex, is delivered to the tumor through capillaries with increased permeability. In tumors, some 67Ga is taken up by tumor cells; some may also be taken up by inflammatory cells when they are present. Gallium-67 binding proteins, such as lactoferrin or ferritin, may also contribute to the accumulation and retention of 67Ga in tumors; however, their roles are less clear. The intensity of these various factors determine their relative contribution and the degree of 67Ga accumulation in tumors.

Topics: Animals; Capillary Permeability; Ferritins; Gallium Radioisotopes; Humans; In Vitro Techniques; Lactoferrin; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Protein Binding; Rats

Topics: 5'-Nucleotidase; Animals; Antibody-Dependent Cell Cytotoxicity; Colony-Stimulating Factors; Cytoskeleton; Histocompatibility Antigens Class II; Humans; Lactoferrin; Lectins, C-Type; Lymphokines; Lysosomes; Macrophage Activation; Macrophages; Mannose Receptor; Mannose-Binding Lectins; Mitochondria; Neoplasms; Nucleotidases; Organoids; Oxygen; Phagocytosis; Receptors, Cell Surface; Receptors, Complement; Receptors, Fc; Receptors, Immunologic; Receptors, Transferrin

The large number of publications dealing with biokinetics, metabolism and factors influencing tissue uptake of 67Ga-citrate could not clarify the mechanism responsible for the uptake of this compound into tumor tissue. The present paper reviews biokinetic data obtained from clinical investigations and animal experiments and briefly points out some possible pathways of the mechanism for gallium localisation in tumors as well as in abscesses and inflammatory lesions.

Topics: Animals; Blood Proteins; Fasting; Female; Gallium Radioisotopes; Humans; Kinetics; Lactation; Lactoferrin; Male; Maternal-Fetal Exchange; Mice; Milk, Human; Neoplasms; Pregnancy; Protein Binding; Radiation Dosage; Rats; Tissue Distribution; Transferrin; Whole-Body Irradiation

Topics: Animals; Conalbumin; Forecasting; Infection Control; Infections; Iron; Lactoferrin; Neoplasms; Transferrin; Vertebrates

Topics: Animals; Bacterial Infections; Gallium Radioisotopes; Humans; Infections; Lactoferrin; Leukocytes; Neoplasms; Radionuclide Imaging

We evaluated safety and activity of talactoferrin, a novel immunomodulatory protein in a phase IB trial of patients with refractory solid tumors.. Thirty-six patients with metastatic cancer who had progressed on, or were ineligible for, standard chemotherapy received single-agent oral talactoferrin. Following dose-escalation, with no DLTs , patients were randomized to 4.5 or 9 g/day talactoferrin.. Talactoferrin was well tolerated with apparent anti-cancer activity, particularly in NSCLC and RCC. One patient had a PR (RECIST) and 17 patients (47%) had stable disease (50% disease control rate). Median PFS in the twelve NSCLC and seven RCC patients was 4.2 and 7.3 months, respectively. There was no apparent difference in anti-tumor activity or adverse events between talactoferrin doses.. Oral talactoferrin was well tolerated. Although evaluated in a small number of patients, talactoferrin appeared to have anti-cancer activity, particularly in NSCLC and RCC and should be evaluated further.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Cell Proliferation; Demography; Female; Humans; Kidney Neoplasms; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Tomography, X-Ray Computed

Advanced-stage cancer patients often suffer from anemia that closely resembles the anemia of chronic inflammatory diseases characterized by specific changes in iron homeostasis and absorption. i.v. iron improves the efficacy of recombinant human erythropoietin (rHuEPO) in anemic cancer patients undergoing chemotherapy. We report the results of an open-label, randomized, prospective trial aimed at testing the efficacy and safety of treatment with oral lactoferrin versus i.v. iron, both combined with rHuEPO, for the treatment of anemia in a population of 148 advanced cancer patients undergoing chemotherapy. All patients received s.c. rHuEPO-beta, 30,000 UI once weekly for 12 weeks, and were randomly assigned to ferric gluconate (125 mg i.v. weekly) or lactoferrin (200 mg/day). Both arms showed a significant hemoglobin increase. No difference in the mean hemoglobin increase or the hematopoietic response, time to hematopoietic response, or mean change in serum iron, C-reactive protein, or erythrocyte sedimentation rate were observed between arms. In contrast, ferritin decreased in the lactoferrin arm whereas it increased in the i.v. iron arm. In conclusion, these results show similar efficacy for oral lactoferrin and for i.v. iron, combined with rHuEPO, for the treatment of anemia in advanced cancer patients undergoing chemotherapy.

Topics: Administration, Oral; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Female; Ferric Compounds; Hemoglobins; Humans; Lactoferrin; Male; Neoplasms; Prospective Studies; Quality of Life; Recombinant Proteins; Treatment Outcome

Lactoferrin is an iron-binding glycoprotein first identified in breast milk as a protein product of mammary epithelial cells. Its immunomodulatory functions include activation of NK and lymphokine-activated killer cells and enhancement of PMN and macrophage cytotoxicity. Studies in animal models have shown promising anti-cancer activity. The purpose of the present study was to evaluate the safety and tolerability of talactoferrin alfa (talactoferrin; TLF) in humans, as well as pharmacokinetics and pharmacodynamics.. Ten adult patients with progressive advanced solid tumors who had failed conventional chemotherapy were administered oral TLF at doses from 1.5 to 9 g/day, using a 2 weeks on, 2 weeks off schedule. Patients were evaluated for drug toxicity, tumor growth rate, talactoferrin pharmacokinetics and cytokine markers.. Talactoferrin was very well tolerated. No hematological, hepatic, or renal toxicities were reported. A single patient had Grade 2 diarrhea, and there were no Grade 3 or 4 toxicities. Following oral administration, significant levels of talactoferrin were undetectable in circulation, but a statistically significant increase in circulating IL-18, a pharmacodynamic indicator of talactoferrin activity, was observed. Of the eight patients who were radiologically evaluable, five (63%) had stable disease by RECIST criteria two months after start of therapy, including one patient with a minor response. Seven patients (88%) had a decrease in their tumor growth rate. The three patients with non-small cell lung cancer (NSCLC) all survived for at least one year following the start of talactoferrin monotherapy.. Talactoferrin is a promising, well-tolerated new agent that should be evaluated further in patients with refractory metastatic cancer.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Humans; Interleukin-18; Lactoferrin; Male; Middle Aged; Neoplasms; Recombinant Proteins

The fusion of human serum albumin (HSA) with human lactoferrin (hLF) (designated as hLF-HSA) has improved the pharmacokinetic properties and anti-proliferative activities of hLF against cancer cells. In this study, we evaluated the anti-migratory activities of hLF and hLF-HSA against the human lung adenocarcinoma PC-14 cell line using wound healing and Boyden chamber assays. Despite the unexpected hLF-induced migration, hLF-HSA clearly demonstrated the complete inhibition of PC-14 cell migration. To examine the mechanism underlying the enhanced PC-14 cell migration by hLF alone but suppressed migration by hLF-HSA, we focused on the matrix metalloproteinase (MMP) family of endopeptidases because MMPs are often reported to play important roles in facilitating the migration and metastasis of cancer cells. Furthermore, hLF is a transactivator of MMP1 transcription. As expected, treatment of cells with hLF and hLF-HSA led to the upregulation and downregulation of MMP1, respectively. In contrast, MMP9 expression levels, which are often associated with cancer migration, were unchanged in the presence of either protein. An MMP inhibitor attenuated hLF-induced migration of PC-14 cells. Therefore, specific enhancement and suppression of MMP1 expression by hLF and hLF-HSA have been implicated as causes of a marked increase and decrease in PC-14 cell migration, respectively. In conclusion, the fusion of HSA with hLF (hLF-HSA) promoted its anti-migratory effects against cancer cells. Therefore, hLF-HSA is a promising anti-cancer drug candidate based on its improved anti-migratory activity towards cancer cells.

Topics: Albumins; Cell Movement; Down-Regulation; Humans; Lactoferrin; Matrix Metalloproteinase 1; Neoplasms; Recombinant Fusion Proteins

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

Topics: Antineoplastic Agents; Drug Delivery Systems; Gallium; Humans; Lactoferrin; Nanoparticles; Neoplasms; Tumor Microenvironment

Topics: Apoptosis; Caco-2 Cells; Humans; Lactoferrin; Nanoparticles; Neoplasms; Selenium

Taste and smell abnormalities (TSA) are common in patients receiving chemotherapy and may lead to altered nutritional intake, treatment withdrawal, and impaired quality of life. Lipid peroxidation in the oral cavity is one cause of TSA. Lactoferrin (LFN), an iron-binding salivary protein, reduces production of lipid oxidation byproducts and has been shown to reduce perception of unpleasant flavors. To assess the feasibility of LFN as a treatment for TSA, we conducted pilot investigations among patients with cancer who self-reported TSA following onset of chemotherapy. The primary objective was to assess change in subjective taste and smell perception from baseline to completion of 30 days of LFN supplementation.. Patients were treated with 750 mg LFN daily for 30 days and followed for an additional 30 days without LFN. TSA was measured via the taste and smell questionnaire (TSQ) including taste (score 0-10), smell (score 0-6), and composite scores (0-16) (0 = no TSA) at baseline, day 30, and day 60.. A total of 26 patients enrolled; 19 remained on study at day 30 and 17 at day 60. Baseline mean TSQ scores were 6.5 (taste), 3.1 (smell), and 9.6 (composite). By day 30, mean composite TSQ score improved by 1.7 (p = 0.018); taste and smell improved by 0.6 (p = 0.062) and 1.1 (p = 0.042), respectively. From baseline to day 60, mean composite TSQ score improved by 3.8 (p < 0.0001); taste and smell improved by 1.9 (p = 0.001) and 1.8 (p = 0.003).. Further evaluation of LFN is warranted to determine its value for improving self-reported TSA among patients receiving chemotherapy.

Topics: Dietary Supplements; Humans; Lactoferrin; Neoplasms; Olfaction Disorders; Quality of Life; Smell; Taste; Taste Disorders

The milk-derived bovine lactoferrin (bLf) is an iron-binding glycoprotein with remarkable selective anticancer activity towards highly metastatic cancer cells displaying the proton pump V-ATPase at the plasma membrane. As studies aiming to dissect the bLf mechanisms of action are critical to improve its efficacy and boost its targeted clinical use, herein we sought to further uncover the molecular basis of bLf anticancer activity. We showed that bLf co-localizes with V-ATPase and cholesterol-rich lipid rafts at the plasma membrane of highly metastatic cancer cells. Our data also revealed that bLf perturbs cellular trafficking, induces intracellular accumulation of cholesterol and lipid rafts disruption, downregulates PI3K, and AKT or p-AKT and inhibits glycolysis of cancer cells harbouring V-ATPase at the plasma membrane lipid rafts. Altogether, our results can lay the foundation for future bLf-based targeted anticancer strategies as they unravel a novel cascade of molecular events that explains and further reinforces bLf selectivity for cancer cells displaying plasmalemmal V-ATPase.

Topics: Adenosine Triphosphatases; Antineoplastic Agents; Cell Membrane; Cholesterol; Glycolysis; Iron; Lactoferrin; Membrane Microdomains; Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proton Pumps

Despite the active research towards introducing novel anticancer agents, the long-term sequelae and side effects of chemotherapy remain the major obstacle to achieving clinical success. Recent cancer research is now utilizing the medicinal chemistry toolbox to tailor novel 'smart' carrier systems that can reduce the major limitations of chemotherapy ranging from non-specificity and ubiquitous biodistribution to systemic toxicity. In this aspect, various stimuli-responsive polymers have gained considerable interest due to their intrinsic tumor targeting properties. Among these polymers, poly(N-isopropylacrylamide (PNIPAM) has been chemically modified to tune its thermoresponsivity or even copolymerized to endow new stimulus responsiveness for enhancing tumor targeting. Herein, we set our design rationale to impart additional active targeting entity to pH/temperature-responsive PNIPAM-based polymer for more efficient controlled payloads accumulation at the tumor through cellular internalization via synthesizing novel "super intelligent" lactoferrin conjugated PNIPAM-acrylic acid (LF-PNIPAM-co-AA) copolymer. The synthesized copolymer was physicochemically characterized and evaluated as a smart nanocarrier for targeting breast cancer. In this regard, Honokiol (HK) was utilized as a model anticancer drug and encapsulated in the nanoparticles to overcome its lipophilic nature and allow its parenteral administration, for achieving sustainable drug release with targeting action. Results showed that the developed HK-loaded LF-PNIPAM-co-AA nanohydrogels displayed high drug loading capacity reaching to 18.65 wt.% with excellent physical and serum stability. Moreover, the prepared HK-loaded nanohydrogels exhibited efficient in vitro and in vivo antitumor activities. In vivo, HK-loaded nanohydrogels demonstrated suppression of VEGF-1 and Ki-67 expression levels, besides inducing apoptosis through upregulating the expression level of active caspase-3 in breast cancer-bearing mice. Overall, the developed nanohydrogels (NGs) with pH and temperature responsivity provide a promising nanocarrier for anticancer treatment.

Topics: Acrylic Resins; Animals; Drug Carriers; Hydrogen-Ion Concentration; Lactoferrin; Mice; Neoplasms; Polymers; Temperature; Tissue Distribution

Human lactoferrin (hLF), a soluble factor of the innate immune system, exhibits various biological functions and therefore has potential as a therapeutic protein. However, the clinical applications of hLF are limited by its low stability in blood. We therefore attempted to resolve this by producing recombinant hLF fused to human serum albumin (HSA). Two HSA-fused hLFs with different fusion orientations (hLF-HSA and HSA-hLF) were produced in Chinese hamster ovary (CHO) DG44 cells. hLF-HSA revealed higher thermal stability, resistance to peptic degradation, and stability during the process of cellular uptake and release in an intestinal enterocyte model (Caco-2 cells) than HSA-hLF. The lower stability of HSA-hLF is presumably due to the steric hindrance imposed by HSA fusion to the N-terminus of hLF. Both HSA fusion proteins, especially HSA-hLF, displayed improved pharmacokinetic properties despite the lower protein stability of HSA-hLF. hLF-HSA and HSA-hLF exhibited approximately 3.3- and 20.7-fold longer half-lives (64.0 and 403.6 min), respectively, than holo-rhLF (19.5 min). Both HSA fusion proteins were found to exert enhanced growth inhibition effects on cancer cells in vitro, but not normal cells. Their enhanced growth inhibitory activities were considered to be due to the synergetic effects of hLF and HSA because hLF alone or HSA alone failed to exert such an effect. Altogether, Fusion of HSA to hLF yielded superior pharmacokinetics and anti-proliferative activities against cancer cells. HSA-fused hLF is a novel candidate for further application of hLF as biopharmaceuticals for intravenous administration.

Topics: Albumins; Animals; Caco-2 Cells; CHO Cells; Cricetinae; Cricetulus; Humans; Lactoferrin; Neoplasms; Recombinant Fusion Proteins

Lactoferrin (Lf) is an iron-binding glycoprotein protein known to have immune-modulatory role and recently, its anticancerous effect against different cancer cell types was emphasized. In the present investigation, a comparative evaluation of anticancer potential of colostrum-derived lactoferrin from Indian native zebu cow (Sahiwal, SAC), crossbred (Karan Fries, KFC) and commercially available (C-Lf) lactoferrin from exotic cow using cellular models was made. A protocol was standardized successfully to purify Lf protein from colostrum of both breeds using HPLC and purity was confirmed by LC-MS. A standardized dose of 750 µg/mL Lf was used to treat two cell types MDA-MB-231 and MCF-7 with Lf from three different sources; SAC-Lf, KFC-Lf and C-Lf for 48 h and 72 h. Different cellular parameters including cytotoxicity, viability, apoptosis and cell proliferation were determined. Comparatively, Lf from commercial source (C-Lf) had maximum effect in both cell types followed by SAC-Lf and KFC-Lf. Further, transcriptional changes in genes associated with apoptosis (

Topics: Animals; Apoptosis; Body Fluids; Cattle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromatography, High Pressure Liquid; Colostrum; Disease Progression; Humans; Lactoferrin; Mass Spectrometry; MCF-7 Cells; Milk; Neoplasms; Transcription, Genetic

Hypoxic microenvironments in the solid tumor play a negative role in radiotherapy. Holo-lactoferrin (holo-Lf) is a natural protein, which acts as a potential ligand of transferrin receptor (TfR). In this work, an anticancer drug, doxorubicin (Dox)-loaded liposome-holo-Lf nanocomposites, is developed for tumor targeting and imaging guided combined radiochemotherapy. Dox-loaded liposome-holo-Lf (Lf-Liposome-Dox) nanocomposites exhibit significant cellular uptake likely owing to the TfR receptor-mediated targeting accumulation of Lf-Liposome-Dox nanocomposites. Additionally, the nanocomposites exhibit high accumulation in the tumor site after intravenous injection as evidenced from in vivo fluorescence imaging. More importantly, it is found that the holo-Lf has the ability to catalyze the conversion of hydrogen peroxide (H

Topics: Animals; Cell Death; Cell Line, Tumor; Chemoradiotherapy; Female; Lactoferrin; Liposomes; Mice, Inbred BALB C; Neoplasms; Tumor Burden; Tumor Hypoxia

Remodeling tumor immune microenvironment (TIME) is an important strategy to lift the immunosuppression and achieve immune normalization. In this work, a mannosylated lactoferrin nanoparticulate system (Man-LF NPs) is developed for dual-targeting biomimetic codelivery of shikonin and JQ1 via the mannose receptor and LRP-1 that are overexpressed in both cancer cells and tumor-associated macrophages. The Man-LF NPs can serve as multitarget therapy for inducing immune cell death in the cancer cells, repressing glucose metabolism and repolarizing tumor-associated macrophages, and consequently, lead to remodeling the TIME (e.g., promotion of dendritic cell maturation and CD8

Topics: Azepines; Biomimetics; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Dendritic Cells; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Lactoferrin; Lectins, C-Type; Low Density Lipoprotein Receptor-Related Protein-1; Macrophages; Mannose; Mannose Receptor; Mannose-Binding Lectins; Nanoparticles; Naphthoquinones; Neoplasms; Receptors, Cell Surface; Triazoles; Tumor Microenvironment

Cationic anticancer peptides, which can induce tumor cell immunogenic death and further promote systemic tumor-specific immune responses, have offered a promising solution to relieve the tumor immunosuppressive microenvironment. However, peptide drugs are easily degraded and lack of targeting ability when administered systemically, leading to limitations in their applications. Herein, we report a pH and thermal dual-sensitive bovine lactoferricin-loaded (one of the most widely studied cationic anticancer peptides) nanoparticles, which simultaneously exhibited antitumor and immune cell activated effects when applied with microwave thermotherapy, an auxiliary method of immunotherapy. The bovine lactoferricin could be delivered to the tumor site by nanoparticles, be immediately released from nanoparticles in the acidic environment of lysosomes and the thermal condition caused by microwave radiation, and ultimately induce tumor apoptosis with the release of damage-associated molecular patterns (DAMPs). It is worth noting that the strategy of bovine lactoferricin-loaded nanoparticles intravenous injection combined with local microwave thermotherapy not only showed excellent efficacy in relieving tumor growth but also resulted in strong antitumor immunities, which was due to the released bovine lactoferricin under stimulating conditions, and the pool of tumor-associated antigens generated by tumor destruction. In conclusion, this work presents a strategy for tumor treatment based on dual-sensitive bovine lactoferricin-loaded nanoparticles combined with microwave thermotherapy, which may provide a solution for cationic anticancer peptides delivery and improving antitumor immune responses.

Topics: Animals; Antineoplastic Agents; Cattle; Delayed-Action Preparations; Humans; Hydrogen-Ion Concentration; Hyperthermia, Induced; Immunotherapy; Lactoferrin; Mice; Microwaves; Nanoparticles; Neoplasms

Curcumin, a natural polyphenol, exhibits anti-oxidant, anti-inflammatory, anti-neoplastic and chemopreventive properties. In fact, targeting of this natural anticancer agent has received a great deal of attention during the recent years. In this study, we proposed that curcumin conjugation with lactoferrin molecules may lead to a potential drug delivery system targeted toward cancerous cells through both active and passive targeting. In this regard, curcumin conjugated lactoferrin was developed via a carbodiimide-based coupling reaction and the resulting conjugates were appraised for their molecular properties as a potential targeted drug delivery system. The mean diameter of the designed nanostructure was about 165 ± 26 nm with a PDI of 0.308 ± 0.045. The conjugated nanostructures showed a considerably improved cytotoxicity on HCT116 cells as illustrated by MTT assay along with a higher level of cellular uptake. Cellular uptake and targeting capability of conjugated samples were further investigated by confocal microscopy and the conjugated curcumin nanostructures showed an enhanced efficacy compared to curcumin. Furthermore, flow cytometry analysis proved that early apoptosis occurred in HCT116 cell line, after 24 h incubation with conjugated curcumin.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Lactoferrin; Nanoparticles; Neoplasms

Biological-material-functionalized porous monoliths were prepared with lactoferrin and β-cyclodextrin via a click reaction. With the monolith as an extraction medium, a method combined with ICP-MS was developed for the determination of total gallium originating from metabolic residues of orally bioavailable gallium complexes with tris(8-quinolinolato)gallium (GaQ

Topics: Antineoplastic Agents; beta-Cyclodextrins; Gallium; Humans; Lactoferrin; Limit of Detection; Neoplasms; Organometallic Compounds; Oxyquinoline; Polymers; Porosity

The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. In this study, we investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumor while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumors and up to 50% of B16-F10 tumors over one month. The treatment was well tolerated by the animals. These results suggest that these novel lactoferrin- and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy.. Specific targeting of cancer cells should enhance the delivery of chemotherapeutic agents. This is especially true for gene delivery. In this article, the authors utilized a dendrimer-based system and conjugated this with lactoferrin and lactoferricin to deliver anti-tumor genes. The positive findings in animal studies should provide the basis for further clinical studies.

Topics: Administration, Intravenous; Animals; Cell Line, Tumor; Dendrimers; Humans; Lactoferrin; Neoplasms

α-Lactalbumin (α-LA) can bind oleic acid (OA) to form HAMLET-like complexes, which exhibited highly selective anti-tumor activity in vitro and in vivo. Considering the structural similarity to α-LA, we conjectured that lactoferrin (LF) could also bind OA to obtain a complex with anti-tumor activity. In this study, LF-OA was prepared and its activity and structural changes were compared with α-LA-OA. The anti-tumor activity was evaluated by methylene blue assay, while the apoptosis mechanism was analyzed using flow cytometry and Western blot. Structural changes of LF-OA were measured by fluorescence spectroscopy and circular dichroism. The interactions of OA with LF and α-LA were evaluated by isothermal titration calorimetry (ITC). LF-OA was obtained by heat-treatment at pH8.0 with LD50 of 4.88, 4.95 and 4.62μM for HepG2, HT29, and MCF-7 cells, respectively, all of which were 10 times higher than those of α-LA-OA. Similar to HAMLET, LF-OA induced apoptosis in tumor cells through both death receptor- and mitochondrial-mediated pathways. Exposure of tryptophan residues and the hydrophobic regions as well as the loss of tertiary structure were observed in LF-OA. Besides these similarities, LF showed different secondary structure changes when compared with α-LA, with a decrease of α-helix and β-turn and an increase of β-sheet and random coil. ITC results showed that there was a higher binding number of OA to LF than to α-LA, while both of the proteins interacted with OA through van der Waals forces and hydrogen bonds. This study provides a theoretical basis for further exploration of protein-OA complexes.

Topics: Animals; Apoptosis; Cattle; Circular Dichroism; Flow Cytometry; Hep G2 Cells; Humans; Hydrogen Bonding; Lactalbumin; Lactoferrin; Neoplasms; Oleic Acid; Oleic Acids; Protein Structure, Secondary

Several naturally occurring cationic antimicrobial peptides (CAPs), including bovine lactoferricin (LfcinB), display promising anticancer activities. These peptides are unaffected by multidrug resistance mechanisms and have been shown to induce a protective immune response against solid tumors, thus making them interesting candidates for developing novel lead structures for anticancer treatment. Recently, we showed that the anticancer activity by LfcinB was inhibited by the presence of heparan sulfate (HS) on the surface of tumor cells. Based on extensive structure-activity relationship studies performed on LfcinB, shorter and more potent peptides have been constructed. In the present study, we have investigated the anticancer activity of three chemically modified 9-mer peptides and the influence of HS and chondroitin sulfate (CS) on their cytotoxic activity.. Various cell lines and red blood cells were used to investigate the anticancer activity and selectivity of the peptides. The cytotoxic effect of the peptides against the different cell lines was measured by use of a colorimetric MTT viability assay. The influence of HS and CS on their cytotoxic activity was evaluated by using HS/CS expressing and HS/CS deficient cell lines. The ability of soluble HS and CS to inhibit the cytotoxic activity of the peptides and the peptides' affinity for HS and CS were also investigated.. The 9-mer peptides displayed selective anticancer activity. Cells expressing HS/CS were equally or more susceptible to the peptides than cells not expressing HS/CS. The peptides displayed a higher affinity for HS compared to CS, and exogenously added HS inhibited the cytotoxic effect of the peptides.. In contrast to the previously reported inhibitory effect of HS on LfcinB, the present study shows that the cytotoxic activity of small lytic peptides was increased or not affected by cell surface HS.

Topics: Animals; Antimicrobial Cationic Peptides; Apoptosis; Cattle; Cell Line; Chondroitin Sulfates; Erythrocytes; Hemolysis; Heparitin Sulfate; Lactoferrin; Neoplasms; Peptide Fragments; Protein Engineering; Structure-Activity Relationship

The lactoferrin gene is known to be expressed either constitutively or under inducible conditions such as hormonal stimuli or inflammation. Its transcription from alternative promoters leads to two products, lactoferrin (Lf) and delta-lactoferrin (DeltaLf) mRNAs the expressions of which are altered during oncogenesis. The comparison of the two enhancer/promoter regions revealed that the two isoforms might be differentially trans-activated. Nevertheless, concomitant expression of both transcripts has been found in some normal tissues and in a subset of breast cancer cell lines and biopsies. Moreover, we found putative inflammatory response elements in both P1 and P2 promoter regions suggesting that both Lf and DeltaLf might be upregulated under inflammatory stimuli. Therefore, a duplex Taqman gene expression assay has been developed and used to profile mRNA expression of the Lf gene in the case of cancer and under inflammatory conditions. Discrimination between the two transcripts is achieved by using a primer pairs/probe set within exon 1beta for DeltaLf and a primer pairs/probe set within exon 1 and exon 2 for Lf. In this study, we confirmed that Lf/DeltaLf Taqman gene expression assay is a powerful tool to investigate the expression of both Lf and DeltaLf transcripts. We also showed that lymphocytes and leukocytes isolated from fresh human blood expressed an extremely high level of DeltaLf messengers. An extensive series of cancer cell lines has been studied confirming that both P1 and P2 promoter regions of the Lf gene are downregulated or silenced in the case of cancer. Furthermore, using stimulation by bacterial lipopolysaccharides (LPS), we showed that in MDA-MB-231 and HT-29 epithelial cells, Lf expression is strongly increased with a higher expression level in MDA-MB-231 whereas DeltaLf expression is not. These results suggest that the NF-kappaB/cRel response elements present in the P1 promoter region are functional whereas those present in the P2 promoter region are not and show that DeltaLf is not regulated in inflammatory conditions.

Topics: Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Inflammation; Lactoferrin; Lipopolysaccharides; Neoplasms; Promoter Regions, Genetic; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Oral administration of bovine lactoferrin (bLF) inhibits carcinogenesis in the colon and other organs in rats, and lung metastasis in mice. A likely mechanism by which bLF mediates its anticarcinogenesis effects is by enhanced expression of cytokines and subsequent activation of immune cells. Oral administration of bLF enhances expression of interleukin-18 (IL-18) mRNA in the mucosa of the small intestine of mice. Importantly, the pepsin hydrolysate of bLF (bLFH) also induced expression of IL-18 mRNA in the mouse small intestine and a peptide produced by pepsin digestion of bLF, bovine lactoferricin (bLFcin), induced expression of mature IL-18 in organ culture. In addition to IL-18, bLF and bLFcin both induced significant increases in caspase-1 activity in peritoneal macrophages and in organ cultures. The increase of mature IL-18 by macrophages was inhibited by caspase-1 inhibitor: caspase-1 is known to cleave the proform of IL-18 to produce active mature IL-18. Finally, bLF also induced expression of IFNgamma by peritoneal macrophages. Importantly, in IFNgamma knockout (GKO) mice, bLF administration resulted in increased expression of caspase-1 protein, but induction of IL-18 mRNA, caspase-1 activity, and mature IL-18 was not observed. These results indicate that orally administered bLF can induce expression of IFNgamma and caspase-1 in the small intestine. IFNgamma in turn increases expression of target genes, including IL-18. Active caspase-1 then cleaves pro-IL-18 to generate mature IL-18. Thus, bLF activates an effector pathway mediated by IFNgamma, caspase-1, and IL-18. We also show that ingested bLF is able to activate more than a single effector pathway. For example, in GKO mice while bLF administration could not activate the IFNgamma/caspase-1/IL-18 effector pathway, it was able to inhibit tumor growth and metastasis by activation of an IFNalpha/IL-7 effector pathway.

Topics: Animals; Blotting, Western; Caspase 1; Caspase Inhibitors; Cattle; Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Immunohistochemistry; In Vitro Techniques; Interleukin-15; Interleukin-18; Interleukin-7; Intestinal Mucosa; Intestine, Small; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasms; Polymerase Chain Reaction

Immunodiffusion assays were used to examine lactoferrin (LF) in the mixed saliva of 1026 patients and 553 apparently healthy individuals. Elevated salivary LF levels were found in respiratory and digestive diseases and diabetes. It is concluded that this non-invasive immunochemical assay is promising in the screening and monitoring of persons during their health examination.

Topics: Adult; Biomarkers; Diabetes Mellitus; Digestive System Diseases; Female; Humans; Lactoferrin; Male; Middle Aged; Neoplasms; Respiratory Tract Diseases; Saliva; Young Adult

Topics: Animals; Carrier Proteins; Cytokines; Graft vs Host Disease; Humans; Immunotherapy; Inflammation; Lactoferrin; Neoplasms; Neovascularization, Pathologic; Proteasome Endopeptidase Complex; RNA-Binding Proteins

Cationic antimicrobial peptides (CAPs) with antitumor activity constitute a promising group of novel anticancer agents. These peptides induce lysis of cancer cells through interactions with the plasma membrane. It is not known which cancer cell membrane components influence their susceptibility to CAPs. We have previously shown that CAPs interact with the two glycosaminoglycans (GAGs), heparan sulfate (HS) and chondroitin sulfate (CS), which are present on the surface of most cells. The purpose of this study was to investigate the role of the two GAGs in the cytotoxic activity of CAPs.. Various cell lines, expressing different levels of cell surface GAGs, were exposed to bovine lactoferricin (LfcinB) and the designer peptide, KW5. The cytotoxic effect of the peptides was investigated by use of the colorimetric MTT viability assay. The cytotoxic effect on wild type CHO cells, expressing normal amounts of GAGs on the cell surface, and the mutant pgsA-745, that has no expression of GAGs on the cell surface, was also investigated.. We show that cells not expressing HS were more susceptible to CAPs than cells expressing HS at the cell surface. Further, exogenously added heparin inhibited the cytotoxic effect of the peptides. Chondroitin sulfate had no effect on the cytotoxic activity of KW5 and only minor effects on LfcinB cytotoxicity.. Our results show for the first time that negatively charged molecules at the surface of cancer cells inhibit the cytotoxic activity of CAPs. Our results indicate that HS at the surface of cancer cells sequesters CAPs away from the phospholipid bilayer and thereby impede their ability to induce cytolysis.

Topics: Animals; Cattle; Cell Line, Tumor; Chlorates; CHO Cells; Cricetinae; Cricetulus; Drug Synergism; Heparin; Heparitin Sulfate; HT29 Cells; Humans; Lactoferrin; Lymphoma; Neoplasms; Peptide Fragments; Protein Structure, Secondary

We have previously shown that talactoferrin-alfa (TLF), a recombinant human lactoferrin, is an immunomodulatory protein that is active against implanted tumors, both as a single agent and in combination with chemotherapy. In this study, we show that talactoferrin is active against autochthonous tumors in a transgenic mouse line, which is more analogous to human cancers, and identify key mechanistic steps involved in the anticancer activity of oral TLF. BALB/c mice transgenic for the rat neu (ErbB2) oncogene (BALB-neuT) treated with oral TLF showed a significant delay in carcinogenesis, with 60% tumor protection relative to vehicle-treated mice at week 21. Oral TLF also showed tumor growth inhibition in wild-type BALB/c mice implanted with neu(+) mammary adenocarcinoma, with one third displaying a long-lasting or complete response. Oral TLF induces an increase in intestinal mucosal IFN-gamma production and an increase in Peyer's patch cellularity, including expansion of CD8(+) T lymphocytes and NKT cells, and the enhancement of CD8(+) T-cell cytotoxicity. In IFN-gamma knockout mice, there is an absence of the TLF-induced Peyer's patch cellularity, no expansion of CD8(+) T lymphocytes and NKT cells, and loss of TLF anticancer activity. TLF antitumor activity is also lost in mice depleted of CD8(+) T cells and in CD1 knockout mice, which lack NKT activity. Thus, the inhibition of distant tumors by oral TLF seems to be mediated by an IFN-gamma-dependent enhancement of CD8(+) T- and NKT cell activity initiated within the intestinal mucosa.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Female; Interferon-gamma; Killer Cells, Natural; Lactoferrin; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; Peyer's Patches; Receptor, ErbB-2

The lactoferrin protein possesses antimicrobial and antiviral activities. It is also involved in the modulation of the immune response. In a normal healthy individual, lactoferrin plays a role in the front-line host defense against infection and in immune and inflammatory responses. Whether genomic variations, such as single nucleotide polymorphisms (SNPs), have an effect on the structure and function of lactoferrin protein and whether these variations contribute to the different susceptibility of individuals in response to environmental insults are interesting health-related issues. In this study, the lactoferrin gene was resequenced as part of the Environmental Genome Project of the National Institute of Environmental Health Sciences, which operates within the National Institutes of Health. Ninety-one healthy donors of different ethnicities were used to establish common SNPs in the exons of the lactoferrin gene in the general population. The data will serve as a basis from which study the association of lactoferrin polymorphism and disease.

Topics: Ethnicity; Female; Gene Frequency; Humans; Lactoferrin; Male; Neoplasms; Open Reading Frames; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly inhibits lung metastatic colony formation, and that this inhibition was possibly due to the activation of T and NK cells. Furthermore, we found that interleukin-18 (IL-18) is induced in epithelial cells of the small intestine by bLF. The present study was undertaken to confirm cytokine production in response to bLF and to assess the underlying mechanisms. Markedly elevated IL-18 levels were found in the small intestine 1-3 h after a single administration of bLF, its pepsin hydrolysate (bLFH), or bTF. Importantly, while IL-18 was significantly increased after a regimen of seven daily administrations of bLF or bLFH, administration of bTF over the course of seven days had little or no effect. In addition to IL-18, a significant increase in caspase-1 activity and interferon-gamma (IFN-gamma) was found in the small intestine after administration of bLF. Similarly, in peritoneal macrophages, bLF markedly enhanced caspase-1 activity and IL-18 levels. Finally, a caspase-1 inhibitor significantly decreased bLF mediated induction of IL-18 in vitro. (bTF had no effect on either caspase-1 or IFN-gamma or on IL-18 in vitro.) These results demonstrate the possibility that elevation of caspase-1 activity by bLF and its hydrolysate may be important for production of mature IL-18 in vivo, and thus in potentiating the killing activity of T and NK cells against tumor cells.

Topics: Administration, Oral; Amino Acid Chloromethyl Ketones; Animals; Caspase 1; Caspase Inhibitors; Cattle; Cells, Cultured; Cysteine Proteinase Inhibitors; Cytokines; Hydrolysis; Interferon-gamma; Interleukin-18; Intestinal Mucosa; Intestines; Lactoferrin; Macrophages, Peritoneal; Male; Mice; Mice, Inbred BALB C; Neoplasms; Pepsin A

A number of shortened derivatives of the lactoferrin model peptide L12, PAWRKAFRWAKRMLKKAA, were designed in order to elucidate the structural basis for antitumour activity of lactoferrin derivatives. Three tumour cell lines were included in the study and toxicity determined by measuring lysis of human red blood cells and fibroblasts. The results demonstrated a strong correlation between antitumour activity and net positive charge, in which a net charge close to +7 was essential for a high antitumour activity. In order to increase the antitumour activity of the shortest peptide with a net charge less than +7, the hydrophobicity had to be increased by adding a bulky Trp residue. None of the peptides were haemolytic, but toxicity against fibroblasts was observed. However, modifications of the peptides had a higher effect on reducing fibroblast toxicity than antitumour activity and thereby resulted in peptides displaying an almost 7-fold selectivity for tumour cells compared with fibroblasts. The antimicrobial activity against the Gram-negative bacteria Escherichia coil and the Gram-positive bacteria Staphylococcus aureus was also included in order to compare the structural requirements for antitumour activity with those required for a high antimicrobial activity. The results showed that most of the peptides were highly active against both bacterial strains. Less modification by shortening the peptide sequences was tolerated for maintaining a high antitumour activity and selectivity compared with antimicrobial activity. The order of the amino acid residues and thereby the conformation of the peptides was highly essential for antitumour activity, whereas the antimicrobial activity was hardly influenced by changes in this parameter. Thus, in addition to a certain net positive charge and hydrophobicity, the ability to adopt an amphipathic conformation was a more critical structural parameter for antitumour activity than for antimicrobial activity, and implied that a higher flexibility or number of active conformations was tolerated for the peptides to exert a high antimicrobial activity.

Topics: Amino Acid Sequence; Animals; Anti-Infective Agents; Antineoplastic Agents; Cell Line, Tumor; Escherichia coli; Humans; Lactoferrin; Mice; Models, Molecular; Neoplasms; Peptides; Staphylococcus aureus; Structure-Activity Relationship

This report provides the first proteomic analysis of normal ovine lymph. By establishing the fact that lymph is more than an ultrafiltrate of blood plasma, it documents that the lymph proteome contains an array of proteins that differentiates it from plasma. The protein chip technology, surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS), two-dimensional gel electrophoresis (2-D PAGE) and MS, were employed to examine the protein expression profiles of ovine lymph. Using a weak cation exchange chip surface to assay lymph and plasma samples by SELDI-TOF-MS showed that the analysis of peak maps from lymph contained three protein peaks that were found only in lymph, while analysis of peak maps from plasma samples showed that five protein peaks were found only in plasma. Lymph and plasma samples showed eight peaks that were common to both. There were also more ions present in plasma than in lymph, which is consistent with the 2-D PAGE analysis. MS analysis of a large number of protein spots from 2-D PAGE gels of lymph produced MS/MS sequences for 18 proteins that were identified by searching against a comprehensive protein sequence database. As in plasma, large protein spots of albumin dominated the protein pattern in lymph. Other major proteins identified in 2-D PAGE gels of lymph included, fibrinogen alpha- and beta-chains, immunoglobulin G (IgG) heavy chain, serotransferrin precursor, lactoferrin, and apolipoprotein A-1. Two proteins that were identified and were differentially expressed in lymph were glial fibrillary astrocyte acidic protein and neutrophil cytosol factor-1. By bringing the technologies of proteomics to bear on the analysis of lymph, it is possible to detect proteins in lymph that are quantitatively and qualitatively differentially expressed from those of plasma.

Topics: Animals; Apolipoprotein A-I; Biomarkers, Tumor; Cattle; Databases as Topic; Electrophoresis, Gel, Two-Dimensional; Glial Fibrillary Acidic Protein; Humans; Hydrogen-Ion Concentration; Isoelectric Focusing; Lactoferrin; Lymph; Mass Spectrometry; NADPH Oxidases; Neoplasm Metastasis; Neoplasms; Peptides; Phosphoproteins; Proteome; Proteomics; Sheep; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Transferrin

Recent studies have demonstrated that bovine lactoferrin (bLF) suppresses tumor growth and metastasis in the mouse and rat and moreover may inhibit angiogenesis. To determine whether angiogenesis inhibition might contribute to antitumor activity, we examined the influence of bLF on tumor-induced angiogenesis and endothelial cell functions as well as angiogenesis-related cytokine production. Bovine LF exhibited dose-dependent inhibition of angiogenesis on 4-6-day-old chick embryo chorioallantoic membranes (CAMs) that lack a mature immune response. This inhibition was reversed when bLF was simultaneously treated with basic fibroblast growth factor (bFGF). It also inhibited in vitro formation of tube-like structures of mouse endothelial KOP2.16 cells. Moreover, it potently suppressed bFGF- or VEGF-induced proliferation of mouse endothelial KOP2.16 cells, but not of mouse fibroblast A31 cells and Lewis lung carcinoma (3LL) cells. In mice, both orally and intraperitoneally administered bLF significantly and dose-dependently suppressed 3LL cell-induced angiogenesis in a dorsal air sac assay. As orally administered bLF was reported to exhibit antitumor activity through production of interferon (IFN)-gamma and interleukin (IL)-18 in intestinal mucosa (Kuhara T et al., Nutr Cancer 2000;38:192-9), production of these cytokines in mouse serum and peritoneal macrophages by bLF was examined. IFN-gamma was not detected in serum by bLF administration. However, bLF markedly elevated IL-18 concentration in serum by oral administration, but not by intraperitoneal administration. It also induced IL-18 in peritoneal macrophages in vitro. These results suggest that bLF participates as a regulator of angiogenesis, possibly explained by blocking endothelial function and inducing IL-18 production. Antitumor activity of bLF may thus be partly mediated by angiogenesis inhibition.

Topics: Administration, Oral; Animals; Cattle; Chick Embryo; Cytokines; Dose-Response Relationship, Drug; Endothelial Cells; Female; Infusions, Parenteral; Interleukin-18; Lactoferrin; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Neoplasms; Neovascularization, Pathologic

We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly increases CD4(+) and CD8(+) T cells and NK (asialoGM1(+) ) cells in the blood of tumor-bearing mice and enhances anti-metastatic activity. In this paper, we document that oral administration of bLF and bLF-hydrolysate (bLFH) is associated with strong increases in CD4(+) and CD8(+) T, as well as asialoGM1(+) cells in lymphoid tissues and lamina propria of the small intestine in mice, especially in tumor-bearing animals in which Co26Lu cells were implanted subcutaneously. Moreover, IgM(+) and IgA(+) B cells in lamina propria of the small intestine were also significantly increased by bLF and bLFH. Bovine apo-transferrin (bTF) did not exhibit such activity. In the colon, only CD8(+) cells were significantly increased by treatment with bLF, while asialoGM1(+) cells were significantly decreased. bLF and bLFH induced cytokines to activate T, B and asialoGM1(+) cells. Administration of bLF and bLFH, but not bTF, increased production of interleukin-18 (IL-18), interferon-gamma (IFN-gamma) and caspase-1 in the mucosa of the small intestine. Particularly high levels of IL-18 were found in the epithelial cells of the small intestine. Moreover, administration of bLF and bLFH, but not bTF, induced IFN-gamma presenting cells in the small intestine. Caspase-1, which processes proIL-18 to mature IL-18, was also induced in the epithelial cells of the small intestine following treatment with bLF and bLFH, but not with bTF. These results suggest that enhanced production of IL-18 and IFN-gamma and caspase-1 induction by treatment with bLF may be important for elevation of intestinal mucosal immunity.

Topics: Administration, Oral; Animals; B-Lymphocytes; Caspase 1; Cattle; Immunity, Mucosal; Interferon-gamma; Interleukin-18; Intestinal Mucosa; Intestine, Large; Intestine, Small; Killer Cells, Natural; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Neoplasms; Peptide Fragments; T-Lymphocytes

We recently demonstrated a higher incidence of monocyte esterase deficiency in patients with lymphoproliferative neoplasia and gastrointestinal carcinoma than in the normal population. Using lactoferrin to stimulate monocyte cytotoxicity we have now compared the abilities of esterase positive and esterase deficient monocytes to lyse K562 cells. The esterase deficient monocytes were from normal subjects whose monocytes have consistently failed to show cytochemical esterase staining over 30-72 months and which lack specific monocyte isoenzymes. The esterase positive monocytes were from age and sex matched control subjects. Esterase positive monocytes responded to lactoferrin stimulation by a five-fold increase in cytotoxicity whereas deficient monocytes failed to produce any response. These results indicate a possible defect in cytotoxicity of esterase deficient monocytes and together with the epidemiological findings suggest a link between monocyte esterase deficiency and neoplasia.

Topics: Cells, Cultured; Cytotoxicity, Immunologic; Esterases; Humans; Lactoferrin; Lymphocytes; Monocytes; Neoplasms

Peripheral blood lactoferrin level and leukocyte count were measured by enzyme immunoassay in the sera of 288 normal subjects and 247 patients with malignant tumors of various localization. Normal lactoferrin level has been found 1055 +/- 191.0 ng/ml. In the patients it was changed either higher or lower, irrespective of the tumor site. This has led the authors to a conclusion on the acute phase pattern of the time course of lactoferrin level in oncologic patients. Elevation of lactoferrin level anticipated changes in leukocyte count.

Topics: Female; Humans; Lactoferrin; Leukocyte Count; Male; Neoplasms

Iron, iron-binding capacity, lactoferrin and total protein were determined in the plasma and pleural fluid of 30 patients with cardiac failure (n = 10), infectious/inflammatory disease (n = 9) and metastatic carcinoma (n = 11). In 16 patients pleural transferrin and ferritin was also measured. Plasma iron and total iron-binding capacity were reduced in inflammatory and neoplastic disease, whereas hyposideremia with normal iron-binding capacity was seen in patients with heart failure. Plasma lactoferrin was reduced in metastatic carcinoma. Exudates (protein greater than or equal to 30 g/l; infectious/inflammatory: 9/9, carcinomatous: 10/11) had significantly higher iron, lactoferrin, transferrin and ferritin concentrations than transudates (protein less than 30 g/l; heart failure: 10/10, carcinomatous: 1/11). Statistically, infectious/inflammatory exudates could be distinguished from neoplastic exudates by a higher median iron concentration (non-parametric Wilcoxon-Mann-Whitney test). Overlap of the respective ranges, however, did not allow a clear-cut differential diagnosis in individual cases. Pleural lactoferrin concentrations, on the other hand, correlated with the pleural granulocyte count and nonspecifically reflect the degree of granulocytic inflammation. Positive pleural/plasma correlations of protein and of iron concentrations were found in exudates only. Within exudates and transudates, on the other hand, total protein correlated with transferrin but not with iron concentrations. Therefore, and because of the substantially higher pleural/plasma ratio for iron than for transferrin concentrations, a quantitatively important, non-transferrin bound iron pool in pleural fluids, most probably ferritin, must be assumed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Exudates and Transudates; Ferritins; Heart Failure; Humans; Infections; Iron; Lactoferrin; Metalloproteins; Neoplasms; Pleural Effusion; Transferrin

We have developed a technique that permits evaluation and semi-quantification of iron-binding function in mature neutrophils. Neutrophil iron-binding reactivity (NFeBR) visualized using the iron nitrilotriacetate-acid ferrocyanide technique was rated 0 to 5+ in 100 segmented cells; the ratings were totaled to yield a score (NFeBRS). Males and post-menopausal females had significantly higher NFeBRS than pre-menopausal females. Neonates had low values, and a homogeneous distribution of NFeBR among neutrophils. In pregnancy and acute infection, NFeBRS were significantly increased. In a patient with congenital lactoferrin (Lf) deficiency, the NFeBRS was very low. In Ph1-positive chronic myelogenous leukemia, 13 of 17 patients had low NFeBRS due to decreased NFeBR, which was heterogeneously distributed among mature neutrophils. By ultrastructural analysis of mature neutrophils in two such patients, the stain deposits in FeBR-positive granules were of normal intensity, but the numbers of positive granules were decreased in many cells. NFeBRS were also low in 12 of 23 patients with other myeloproliferative disorders, and in seven of 15 patients with acute non-lymphoblastic leukemia, but in only seven of 63 patients with other neoplasms. NFeBRS were significantly correlated (p less than 0.008) with values of neutrophil Lf content quantified by immunologic assays in a wide variety of conditions and over a broad range of values. These results augment observations of neutrophil Lf made using immunological methods.

Topics: Adult; Age Factors; Cell Compartmentation; Histocytochemistry; Humans; In Vitro Techniques; Iron; Lactoferrin; Leukemia; Myeloproliferative Disorders; Neoplasms; Neutrophils

In this study plasma concentrations of lactoferrin (LF) and C-reactive protein (CRP) are examined in 9 children with different kinds of cancer but without any intercurrent infections. New, sensitive enzyme-linked immunosorbent assay for LF and CRP are described. The samples are drawn before, during, and after the cytotoxic drugs are given. The cytotoxic courses include cis-platinum, vincristine, adriamycin, cytarabine, and methotrexate (6 g/m2/24 h and 33.6 g/m2/24 h). During the infusion of methotrexate 33.6 g/m2 the concentrations of LF are increased, only a small increase of CRP is observed, and for the other groups there is no changes of both parameters.

Topics: Adult; Antineoplastic Agents; Biomarkers; C-Reactive Protein; Child; Enzyme-Linked Immunosorbent Assay; Humans; Lactoferrin; Methotrexate; Neoplasms; Neutrophils

Plasma concentrations of lactoferrin were measured in immediately separated EDTA samples from 5 subjects who had received HLA identical bone marrow transplants for leukaemia or aplastic anaemia and from 7 subjects who were leukopenic as a consequence of chemotherapy for a variety of malignant conditions. Plasma lactoferrin concentrations were found to closely parallel the leucocyte count and were not found to either predict or to antedate leucocyte regeneration. Serial measurements of plasma lactoferrin in a subject with no circulating neutrophils who received a bone marrow graft revealed that the clearance of lactoferrin followed an exponential pattern and had an initial half time of 2.2 h.

Topics: Agranulocytosis; Anemia, Aplastic; Bone Marrow Transplantation; Hematopoiesis; Humans; Kinetics; Lactoferrin; Lactoglobulins; Leukemia; Leukocyte Count; Neoplasms; Neutropenia; Neutrophils

Topics: Bacterial Infections; Clinical Enzyme Tests; Clinical Laboratory Techniques; Humans; Lactoferrin; Lactoglobulins; Neoplasms; Neutrophils; Peroxidase; Peroxidases; Reference Values

An enzyme-linked immunosorbent assay (ELISA) has been used for quantitative determination of lactoferrin (Lf) and alpha-lactalbumin (alpha-La) in human blood serum. The mean concentration of Lf in normal serum was 265 +/- 21 ng/ml and that of alpha-La did not exceed 5 ng/ml. The increased Lf level (above 450 ng/ml) was found in 16 of 30 (53%) patients with gastrointestinal cancer, in 11 of 25 (44%)--with lung cancer, in 13 of 42 (31%)--with breast cancer and more rarely--in other cancer patients. The increased alpha-La level (above 5.0 mg/ml) was found in 5 of 42 patients with breast cancer and very rarely--in other cancer patients. A conclusion is drawn that serological measurements of Lf and alpha-La were of no diagnostic value for breast cancer.

Topics: Blood Donors; Breast Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lactalbumin; Lactoferrin; Lactoglobulins; Neoplasms