Lactoferrin is a glycoprotein of the transferrin family (has the ability to bind to ferric irons). It is found in body secretions like milk, tears, saliva, nasal secretions and in secondary granules of polymorphonuclear cells (neutrophils). Human colostrum (first milk of breast feeding) is the natural source with highest concentration of lactoferrin. Human milk and cow milk are also rich in this protein.
Lactoferrin plays a central role in iron metabolism. It involves in iron transport, delivery of iron into cells and controlling the iron content in body secretions. Cell proliferation, antimicrobial activity and anticancer activity are some of the other known functions of lactoferrin. Antimicrobial activity of transferrin is well described in the literature. Microorganisms are highly dependent on iron as a substrate, essential for DNA synthesis during their cell cycle. One major ability of lactoferrin is sequestration of free iron. Therefore, microorganisms cannot fulfill their desired iron requirement. Suppression of microorganism proliferation enables other cells of the host (human) immune system to attack and destroy them. Thus lactoferrin is a part of the innate immune system and this immunity is mediated through bodily secretions mentioned above. Lactoferrin has the ability to be bound to iron even in low pH environments. This is very important at foci of inflammation where pH might fall even below 4.5. Similar mechanisms have been suggested for the anticancer ability of lactoferrin. Cancer cells are also dividing at a very high rate. The necessity of iron for maintaining of the cell cycle is even higher than that of microorganisms. Therefore, deprivation of iron to cancer cells by lactoferrin ultimately inhibits tumor growth very effectively. New evidence suggests that other complex biological pathways are also involved in cancer protection properties of lactoferrin apart from this basic mechanisms. These multiple functions of lacoferrin are all conducted by specific receptors on the surface of their target cells.
Anticancer activity of lactoferrin has been evaluated in tumor cell lines under both vitro and in vivo conditions. Suppression of the cell cycle (primarily by inhibition of DNA synthesis) has been hypothesized as the main mechanism by which chemotherapeutic effect is brought about.
In one study done by Dr. Xueying Sun and others, lactoferrin was combined with tamoxifen for the treatment of breast cancer. Tamoxifen is an anticancer drug mainly effective against estrogen receptor positive breast cancer. But it also has effects on estrogen receptor negative breast cancers as well. In this study the investigators sought whether lactoferrin has the ability to enhance the therapeutic effect of tamoxifen on estrogen receptor negative breast cancer. Iron saturated bovine lactoferrin was used as an oral feed for female Balb/c mice. There were 2 models in the study; prevention model and treatment model. In the prevention model, an oral lactoferrin diet and tamoxifen injections were started together and 2 weeks later, 4T1 cancer cells were injected into the mammary fat pad of the mice. In the treatment model, only oral lacoferrin diet was started initially. 2 weeks later 4T1 cells were injected and tamoxifen was started only 2 weeks after this. Growth of the tumor, its metastasis, body weight, and levels of interleukin 18 (also called interferon γ inhibitory factor which has the ability to activate cells that has anti-cancer properties) and interferon γ were analyzed. The results were as follows. Tamoxifen which was given weekly, inhibited 4T1 cell proliferation in vitro. In tumor prevention model, lactoferrin diet in combination with tamoxifen caused a 4 day delay in tumor formations and significantly inhibited tumor growth and metastasis to the liver and lung in comparison to untreated controls. The combination therapy was significantly more effective than monotherapy. Lactoferrin reduced the loss of body weight caused by tamoxifen and the effect of the cancer itself. It also prevented the reduction of interleukin 18 and interferon γ in blood. It enhanced the cellular mediators of innate immunity in the gut and cells with anti-cancer ability at the cancer site. Similar beneficial effects were seen on tumor cell viability. The researchers conclude “the results indicate that iron saturated bovine lactoferrin is a potent natural adjuvant capable of augmenting the chemotherapeutic activity of tamoxifen. It could have application in delaying relapse in tamoxifen-treated breast cancer patients who are at risk of developing ER-negative tumors”.
A similar study done by Dr. D. C. Duarte and others evaluated the effect of bovine milk lactoferrin on human breast cancer cell lines, HS578T and T47D. In contrast to the above study, tamoxifen was not used here as an anticancer agent. One portion of cancer cells were treated with increasing concentrations of lactoferrin whereas the control group was not given the compound. According to the results, lactoferrin reduced the cell viability of both cancer cell lines by about 50 percent. And it also increased the apoptosis (cell death) by about 2 fold for both cell lines. Proliferation rates also decreased significantly. Cell migration showed a significant decrease for the T47D cell line, in the presence of the lactoferrin. This study clearly shows that lactoferrin inhibits most processes of cancer progression and metastasis. However this study did not concentrate on the mechanisms involved in anti-cancer action of lactoferrin.
A study carried out by Dr. S. Penco and others evaluated the expression of lactoferrin in human breast cancer cells. Out of 78 samples 31 were found to be negative for mRNA expression. Further analysis revealed an inverse correlation between estrogen receptor expression and lactoferrin expression. This suggests that the expression of lactoferrin in breast cancer is mediated by many mediators via complex mechanisms. Although this study did not look into the therapeutic effects of lactoferrin, the information from this study is important for planning other research of breast cancer treatment.
Another study was conducted by Dr. Xu and others. They evaluated the effect of bovine lacoferrin on stomach cancer. Their main focus was on the apoptosis of cancer cells and the effect on Akt signaling pathway. Akt pathway promotes the survival of cells in response to extracellular signals. The inhibition of this gives an effective way of cancer treatment. In this study, stomach cancer cells were exposed to lactoferrin for 24 and 48 hours. The cell viability was assessed and apoptosis quantified. According to the results, inhibition of cancer cells was seen with both duration of treatments. Atk signaling pathway was in depth evaluated in this study to propose a mechanism for lactoferrin’s antitumor effect. And the researchers identified that the inhibition of Atk pathway and regulatory effects on its downstream proteins resulted in apoptosis of human stomach cancer cells.
Dr. Xiao and others developed a study to investigate the effect of lactoferrin on head and neck cancer cells. The major objective of the study was to identify the molecular mechanisms of lactoferrin induced cell growth inhibition. Growth arrest was seen in three out of four cell lines tested in this study. Moreover, the inhibition of the G0-G1 part of the cell cycle was identified as the mechanism involved in this process.
Dr. N. Sakamoto studied about the effect of lactoferrin on newly established pancreatic cancer developed both in vitro and in vivo. Inhibitory effects were found in cancer cell lines in both these occasions.
Similar studies have been done for other common cancers like prostate, cervical and oral cancers using lactoferrin. And all of them have given promising results. However, further studies need to be carried out in combination with other commonly used chemotherapeutic agents to find the most efficacious combinations of all.