Lactoferrin is a glycoprotein that binds iron to itself, and it comes from the transferrin family, which can be found mainly in the products of the exocrine gland. It was first recorded in 1929. years by Sorensen and others. They discovered the appearance of protein, which contains iron, in cow’s milk. This protein was further studied in 1960. years, and characterized as similar to human serum transferrin. In fact, its affinity for iron is 300 times higher than transferrin. The etymology of Lactoferrin has its roots in the history of its discovery; “Lacto” means milk in Latin, while “Ferrin” means binding iron.
However, Lactoferrin is not found exclusively in breast milk despite its name. It is a product of exocrine glands found in various parts of the human body, such as the respiratory and digestive systems, among others. Systematically, it is also secreted by polymorphonuclear cells. Its role is not limited to iron-binding and iron homeostasis. Studies have highlighted his role in the view of immunity, defense against infections and inflammation, regulation of cell growth, and differentiation and protection against cancer and metastasis development. These findings have shown that lactoferrin’s role has great potential for cancer therapy, its prevention, and treatment.
Carcinogenesis and lactoferrin
Carcinogenesis is a multi-stage mutational process that can take years before a cell becomes carcinogenic. The process is not simple. The human body is not helpless in the fight against carcinogenesis; it is well equipped to detect and kill mutated cells. The mechanism involves gene expression that suppresses the tumor, activating natural killer cells, among other mechanisms. Understanding the nature of carcinogenesis gives us insight that there is ample opportunity to interfere in this process, preventing or even reversing the process of carcinogenesis itself. For years, clinical studies have persistently supported a positive link between diet and health. Our body needs resources that can be synthesized, inherited, or taken through food to fight carcinogenesis. The body gets its energy source, micronutrients, from the food it digests. Therefore, it is logical and empirical to include in our diet anticancer agents, which support and encourage the body’s natural defense mechanisms against carcinogenesis. This chemopreventive agent must be inexpensive and widely available to benefit the entire population.
Promising research is related to Lactoferrin, a protein that serves to prevent cancer. This protein was tested as in vivo (on living organisms) as well in vitro(on partially living or dead organisms usually in a controlled environment in a test tube or petri dish), and in both cases, anticancer properties of the said protein have been reported (Baveye et al., 1999; Brock, 2002; Nuijens et al., 1996; Tsuda et al., 2000, 2002; Ward et al., 2002; Ushida et al., 1999; Sekine et al., 1997a; Iigo et al., 1999; Wang et al., 2000; Matsuda et al., 2006; Pan et al., 2007).
Lactoferrin is a single-stranded protein that binds iron. It can be found mainly excreted by the exocrine gland in the respiratory, reproductive, and digestive systems. Lonnerdal in 2003. noted the appearance of Lactoferrin excreted in breast milk, tears, synovial fluids, saliva, and semen.
Internally, it can be found in blood and plasma, mostly excreted by neutrophils. Neutrophils synthesize lactoferrin during inflammation.
Its protein structure is very similar to transferrin, an iron transporter in the human body, which occurs naturally. However, Lactoferrin differs from transferrin in terms of its higher affinity for iron and its anti-inflammatory and anticancer activity. A study conducted by Baker in 2002. years supported that Lactoferrin has more potent iron retention abilities.
The natural expression of Lactoferrin
The natural expression of Lactoferrin in the human body is both constitutive and inducible. Petekost and Teng were born in 1986. This showed that Lactoferrin is constitutively expressed in the wet mucosa, primarily the respiratory and digestive tract. Its expression can also be induced, for example, in uterine tissue. Lactoferrin expression is estrogen-inducible. In 1997, Close and others argued that the expression of Lactoferrin in mammalian epithelial cells is mediated by changes in cell shape or its cytoskeletal actin configuration. This observation could explain the suppression of Lactoferrin expression in the case of malignancy, where the cell has lost its normal cytoskeletal configuration. Therefore, it indicates the possibility of the need for external supplementation of Lactoferrin in case of malignancy.
Lactoferrin is synthesized by neutrophils and is stored within neutrophil granules. Lactoferrin-containing granules can either be excreted into the blood when stimulated or incorporated into phagosomes (Maher et al., 1993; Van Snick et al., 1974). Lactoferrin secretion into the blood system is induced by various conditions such as increased iron levels in the blood, inflammation, infection, and carcinogenesis. The pathway or regulation of its secretion is multifactorial and will be much better understood and future research. Studies have gathered enough evidence to explain the removal of Lactoferrin from the human body. Olofsson and others, in 1977, argued that its removal involves endocytosis by RES (reticuloendothelial system) cells such as macrophages and monocytes. In 1979, Bennett and Kokocinski proved that the liver and spleen removed labeled Lactoferrin. Hutchens et al., In 1991, proved that Lactoferrin also cleanses the kidneys and excretes it in the urine.
Antibacterial activity of Lactoferrin
The antibacterial activity of Lactoferrin was noted by Santagati et al., 2005. Valenti et al., 1998 and Levay et al., 1995. The main mechanism is by inhibiting bacteria’s growth by reducing the level of iron needed to bacteria multiplied, binding to LPS (lipopolysaccharides) labeling bacteria helping their purity by phagocytes.
Lactoferrin also shows immunomodulatory activity. Dennis et al.. In 2000, they showed that Lactoferrin stimulates the production and increases T and B lymphocytes and NK (killer cells), which later releases various cytokines and therefore increases the phagocytic and cytotoxic activity of RES cells. Adamik et al., 1998, and Bennett et al., 1981, also noted that Lactoferrin accelerates the maturation of lymphocytes, B and T cells, and raises the expression of several types of cell receptors.
Iron and lactoferrin
Iron is a necessary element for cell functioning, especially cell proliferation. The importance of iron to the human body is reflected in our body’s mechanism to take, transport, regulate and store iron to ensure that the body’s needs for iron are always met. All excess iron will be stored intercellularly due to ferritin. The storage mechanism is crucial for keeping free iron in the bloodstream. While iron is essential for cells, high iron levels in the blood paradoxically harm the body. Free iron in the blood creates free radicals that can damage cells, a phenomenon that balances cellular defenses and DNA repair mechanisms.
While iron supplementation is widely accepted today, there have been concerns about potential adverse effects. Weinberg 1984, 1992; Selby and Friedman 1988; Stevens et al., 1988, proved that iron promotes colon and breast carcinogenesis in rats and increases the risk of several cancers in humans. Some evidence also supports the mixing of iron metabolism in breast cancer. In 1982, Weinstein et al. Measured a sixfold increase in the concentration of ferritin in breast cancer tissue relative to normal tissue. Transferrin receptor proteins also increase in breast cancer compared to normal cells. All of this evidence together suggests that iron promotes carcinogenesis in humans. Since cancer cells’ proliferation requires iron, the continuous supplementation of cancer cells with iron through an increase in transferrin receptors will certainly increase the rate of its proliferation.
Anticancer activity of lactoferrin
The anticancer activity of lactoferrin can be attributed to its iron-binding properties. Free radical is a known triggering agent of cancer. It damages the nuclear level, disrupting the nucleic acid structure, a process known as mutation. Since iron is a known creator of free radicals, by cleaning iron from free plasma and keeping it at a low level, Lactoferrin helps prevent the mutational consequences of iron circulating freely. In addition to its preventive properties, Lactoferrin also performs an antiproliferative activity by limiting the availability of iron to cancer cells and limiting their proliferation. This has been observed especially in estrogen-dependent neoplasms such as breast cancer and uterine cancer in studies conducted by Weinstein et al. In 1982 and Elliot et al. In 1993. Iron chelators can prevent later development.
In addition to iron-binding activity, Lactoferrin also performs other anticancer mechanisms. In a study conducted by Damien et al., 1998, and Matsuda et al., 2006, taking Lactoferrin showed that it significantly reduced NK cells’ cytotoxicity. Studies included pre-treatment of NK cells or target cells with Lactoferrin. The results reflected that Lactoferrin alleviated the cytotoxicity of NK cells and the sensitivity of target cells to lysis.
Studies have also shown that Lactoferrin inhibits epithelial cell proliferation by interfering with cell cycle progression. They proved that Lactoferrin induces cell growth arrest from G1 to the S phase. This was performed by modulating the expression and activity of specific regulatory proteins.
Studies in rats involving oral administration of iron-binding lactoferrin have shown that lactoferrin significantly inhibits the VEGF165-mediated angiogenesis response. Therefore, giving rise to the potential use of Lactoferrin as a treatment for angiogenesis.
In another study conducted by Yoo et al., 1997, LFCin, a lactoferrin derivative, was shown to induce apoptosis in THP – 1 human monocyte leukemia cells. The activity was mediated by the modulation of intercellular reactive oxygen species (ROS) and the activation of Ca2 + / Mg2 + dependent endonucleases.
In a recent clinical study conducted by Tarek M. Moastad et al., 2014, related to the therapeutic properties of Lactoferrin in patients with colorectal cancer receiving chemotherapy, parallel randomized controlled trials were conducted in which neither study participants nor study subjects knew which is the control and which is the test group. The results show that oral administration of bovine Lactoferrin has a significant therapeutic effect on patients with colorectal cancer. According to this study, taking Lactoferrin daily showed clinically beneficial effects in patients with colorectal cancer.
Finally, Lactoferrin, an iron-binding protein that occurs naturally and has many beneficial effects, anticancer activity, continuously confirms that it is a potent anticancer agent. Its natural appearance in the body makes it safe, and taking this agent will help the body fight carcinogenesis.