Lactoferrin a multifunctional protein

Milk and dairy products have become recognised as functional foods, suggesting their use has a direct and measureable effect on health outcomes and their consumption has been related with a reduced risk of numerous Cancers. Milk proteins classified upon their availability to the two main groups. First group is called the main proteins which include Casein and two types of Whey proteins called α Lactalbumin and β Lactoglobulin. The second group called minor proteins including Lactoferrin, Immunoglobulins Lactoperoxidase and Lysozyme. Although the second group members are considered as minor proteins but plays a major role directly or indirectly as the first line of defense because of their great ability to work as antimicrobial, antioxidant and anticancer agent.

Lactoferrin was received considerable attention in recent years, to being one of the biologically active compounds which possess actually role as anti microbial, immune modulator, anti inflammatory, antioxidant, and anticancer. Lactoferrin was first isolated from bovine milk in 1939. Lactoferrin is a glycoprotein with a molecular weight of about 80 kDa. Higher levels of Lactoferrin are present in milk and colostrums. The molecular structure and sequence of amino acids (type of protein) in human Lactoferrin were discovered in 1984. The interesting fact about Lactoferrin is its great attraction to attach with iron. Besides iron Lactoferrin is capable of binding a large amount of other compounds and substances even DNA. This is the way in which Lactoferrin affect the metabolism and distribution of various substances. During bacterial infections Lactoferrin binds most of iron which is necessary for growth of bacteria. Lactoferrin is present in blood, plasma or serum in relatively low concentration. In adults the higher concentrations of Lactoferrin are present in milk and colostrums.

The secretions from exocrine glands also contain Lactoferrin. The production of Lactoferrin by human kidneys was also reported. Lactoferrin prevents viruses from entering cells and infection is stopped at an early stage. It is thought to cause a therapeutic revolution, because it was proven in the last few years that it can be used in the treatment of many diseases such as hepatitis, osteoporosis, diabetic foot ulcers and cancer. Most of such studies were conducted on animals. During the viral infections and in many types of inflammatory reactions, an increase in the concentration of Lactoferrin has been observed at the site of infection. It can be categorised as an acute phase protein.

Lactoferrin is able to stop the growth of human mammary carcinoma cells between G and S stage. It inhibits the development of experimental metastasis in mice. Hepatocellular carcinoma is a tumor of the Liver. It is one of the most prevalent types of cancer across the world and constitutes around 79% of all cancers. Hepatocellular Carcinoma (HCC) is the sixth most common cancer globally, attributing to 5. 7%of new cancer cases annually. lt is the third most common cause of cancer related deaths and carries an overall survival rate of only 3. 5%. The incidence of hepatocellular carcinoma increases with age and it is also greatly affected by the geographical conditions may be due to genetic makeup of the inhabitants. HCC is most common in elderly people and more prevalent in black than white. The common risk factors for HCC include Hepatitis B and C virus infection and conditions such as non-alcoholic fatty liver disease, which are associated with obesity. The World Health Organization reported that, in 2012-14. One million people were newly diagnosed with cancer, 8.2 million cancer patients died, and 32. 6 million people were living with cancer (within a 5-year diagnosis) worldwide. This means the incidence of cancer is still very high and that, currently, there is no effective cure, especially in patients at advanced stages of the disease. Therefore, preventing the development of carcinomas is crucial for decreasing the currently high mortality of cancer. Some epidemiological studies have shown that more than two-thirds of cancers could be prevented through the adoption of an appropriate lifestyle. A diet rich in preventive agents is one of the strategies proposed to decrease the incidence of cancer and other diseases. Milk-derived Lactoferrin is considered a functional

protein and reaches a level of 7 g/L in colostrums. The multifunctional Lactoferrin could, thus, play a role in cancer prevention. Indeed, a large number of reports provide clear evidence that oral administration of bovine Lactoferrin can effectively decrease the development of chemically induced cancers in animal models. Bovine Lactoferrin is a relatively stable protein that can be active even after passing through the gastrointestinal tract as partially degraded fragments (derivative peptides). These fragments, with a molecular mass over 20 kDa, contain the receptor-binding regions of the protein as well as the anticancer active regions. An example of these fragments is the Lactoferrin B peptide. Moreover, these fragments can be internalized by specific Lactoferrin receptors in the intestinal brush border membrane. The oral administration of 0.2% or 2% bovine Lactoferrin was found to decrease by 32.5% and 42.5%, respectively, the occurrence of colon carcinogenesis in azoxymethane-treated F344 rats. In a study conducted with the 7, 12-dimethylbenz(a) anthracene-induced hamster buccal pouch model, the incidence of carcinogenesis was reduced by a diet containing 0.2% bovine Lactoferrin. Moreover, oral administration of bovine Lactoferrin showed chemo preventive activity against tongue, esophagus, and lung carcinogenesis in rats.

The suggested chemo preventive effects could be due to the multiple functions of Lactoferrin, which include stimulation of the immune response modulation of the carcinogen-metabolizing enzymes and the oxidant-antioxidant profile in the target organs and inhibition of angiogenesis. Regulation of the immune function by Lactoferrin may be a key factor in the mechanisms of action involved in cancer prevention. Presently, the extraction of bovine Lactoferrin from milk and whey is an industrial reality. Therefore, it is plausible that, in the future, Lactoferrin-containing supplements or the consumption of Lactoferrin-enriched dietary products might be recommended to prevent or delay the onset of cancer.

Although the exact mechanisms involved in the anticancer activity of Lactoferrin are still unclear, they can be generally grouped into extracellular effects, intracellular effects, and immunostimulation. The extracellular effects are related mainly to the interaction of Lactoferrin with the cell membrane and membrane receptors, while the intracellular effects suggested by most studies are related mostly to cell apoptosis and cell cycle arrest. The immunostimulatory action of Lactoferrin is achieved primarily by activating immune cells to release tumor cytotoxic effectors. The proposed mechanisms underlying the cytotoxicity of Lactoferrin or its derivatives against cancer cells are diverse and are derived from in vitro experiments. Moreover, findings from in vivo experiments are generally similar.

Although there is still some uncertainty about the mechanisms underlying the cytotoxicity of Lactoferrin and its derivatives against cancer, there is no doubt about its potential anticancer activity. Since Lactoferrin and its derivatives are food-derived components, and thus nontoxic, they constitute an interesting alternative to chemoprevention and the currently used anticancer drugs. In addition, its stability through the gastrointestinal tract is beneficial if oral administration is envisaged. All of these features are believed to be essential for an efficient drug. To date, several clinical trials have been initiated to evaluate the therapeutic effects of Lactoferrin in cancer therapy, such as for non-small-cell lung cancer. Lactoferrin has been found to be useful for reducing some clinical complications associated with chemotherapy, such as anemia, and immunoreactions stimulated by Lactoferrin is thought to be a key factor in cancer therapy.

Most of the data on the anticancer effects of Lactoferrin are based on in vitro studies, in which Lactoferrin and its derivatives have been shown to greatly inhibit the proliferation of various cancer cells.

This means that their cytotoxicity is probably due to the direct contact between Lactoferrin and cancer cells. Thus, the direct and indirect actions of Lactoferrin should be fully explored so that a greater anticancer effect can be obtained in vivo. The direct action of Lactoferrin can be achieved by intratumoral or intravenous injection. Unfortunately, though, Lactoferrin can be quickly cleared after intravenous administration. In light of this, perhaps a tumor-targeting delivery system, which will prevent the protein from degrading before it reaches the tumor cells, would improve the anticancer effects in vivo. Currently, several carrier vectors, involving systemic targeting as well as intracellular targeting, are available to deliver anticancer agents. Both the widely used liposomes and the emergent nanoparticles have proved to be efficient carriers whose further use in clinical practice is supported. They may be modified with specific ligands to target tumor cells or to just remain in circulation longer, thus providing a slow release of Lactoferrin or its variants, thereby persistently activating the immune system. This approach has the potential to greatly reduce any possible adverse effects and increase the agent’s performance against cancer. In addition, the combination of Lactoferrin and its derivatives with established anticancer agents has been shown to result in increased killing of cancer cells in vitro and should be further explored. With this approach, the first clinical use of Lactoferrin is envisaged as an adjuvant therapeutic agent in cancer patients. This will not only take advantage of the immunotherapeutic effects of Lactoferrin, it will also provide anticancer effects superior to those obtained when chemotherapy agents are used alone.

Pakistan is located in South –Asia where the prevalence of hepatitis B and C is intermediate. In our present project, Lactoferrin was isolated from Mozzarella cheese whey which is a byproduct during the making of cheese. This isolated Lactoferrin was tested in experiments conducted on animals (rats)to study the effectiveness of Lactoferrin against cancer. At the end of the experiments it was concluded that Lf helps greatly to fight against cancer. ln our study Liver cancer was first induced in animals and after two months a comparison was done between different groups of rats in which one group received diet containing Lactoferrin while other group received diet contains no Lactoferrin. ln group which ingested Lactoferrin we observed a significant reduction in degree of cancer development and levels of cancer marker enzymes come to wards normal values as compared to the group in which cancer was induced and received diet without Lactoferrin. Hepatitis C related chronic liver disease has become the major cause of a rising prevalence of HCC in Pakistan. There is a need to implement a proper Surveillance program to pick up the disease early. Lactoferrin has been the focus of intense research of late. Due to its unique antimicrobial, immunomodulatory, antineoplastic, and even anticancer properties, LF seems to have great potential in practical medicine. Restoration of Lactoferrin Gene expression can effectively inhibit the spread of cancer cells. Although clinical trials involving the use of Lactoferrin in cancer therapy are ongoing, there are still no reports about the use of Lf in clinical practices. It is likely that Lactoferrin will continue to be studied for its potential use as primary or adjuvant agent in treatment of cancer.

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