Milk lactoferrin: A nutraceutical supplement for cancer

Introduction
To fight cancer, multiple aspects of therapy are being considered including suppression of side effects, and adjunct and complementary treatments. Many epidemiological studies have revealed the importance of an appropriate lifestyle to prevent cancer. A diet containing anti-cancer agents is proposed to be a suitable strategy to control the risk of cancer (Poullis et al., 2004).
Dairy products especially milk contain many nutritional supplements including proteins, vitamins, and bioactive peptides which are not only beneficial for human health but also reported for their anti-cancer potential. Lactoferrin has been derived from various sources but here the main focus is on lactoferrin derived from milk, especially bovine milk (Sah et al., 2015).

Additionally, the peptides derived from lactoferrin, especially bovine lactoferricin B and holo lactoferrin (an iron-binding form of lactoferrin) have been reported as an anti-cancer agent. Multiple studies have reported the role of lactoferrin in stopping cancer progression via various mechanisms. The silencing or downregulation of lactoferrin genes is associated with cancer metastasis, while restoration of the expression of lactoferrin gene has inhibited the proliferation of cancer cells. Lactoferrin as an oral supplement with concentrations of 0.2 % to 2% showed the inhibition of carcinogenesis in animal models by 32.5 to 42.5% respectively (Adlerova et al., 2008). Moreover, administration of bovine or milk lactoferrin showed preventive activity against multiple types of cancer. Finally, lactoferrin as a drug delivery system has been discussed for the targeted delivery of chemotherapeutic drugs.

 

Milk lactoferrin is effective in cancer
Modulation of cell cycle
Many anti-cancer agents are reported for their potential to arrest the cell cycle and induce cytotoxicity in cancer cells. Lactoferrin has been reported as a selective agent regarding cancerous tissues because of exerts an inhibitory effect on only tumor cells while for the growth of normal cells, lactoferrin is its positive regulator. The molecular mechanism of both bovine and human lactoferrin to enhance the growth of normal cells is due to shortening the cell cycle by upregulation the expression of mRNA of proliferative cell nuclear antigen thus increasing the number of cells in the G2 and S phase of the cycle (Zhang et al., 2014).

Concerning tumor cells, both bovine and human lactoferrin have been reported to arrest cell growth in different phases of the cell cycle. It reported the selectivity of bovine lactoferrin in which bLF blocked the growth of tumors in four breast cancer cell lines but did not inhibit normal cell lines. The authors revealed that the molecular mechanism of bovine lactoferrin for cell cycle arrest was associated with the upregulation of phosphorylated AMPK and the downregulation of mTOR, which is crucial for cell survival (Zhang et al., 2018).

 

Induction of apoptosis
In cancer, besides higher proliferation rate and invasion characteristics, genetic changes accumulating in cells lead to dysregulation in extrinsic and intrinsic pathways and disrupt the balance between pro-apoptotic and anti-apoptotic proteins which confer the cell to evade apoptotic signaling (Cutone et al., 2020).
Lactoferrin has been reported to activate apoptotic signaling in various types of cancers. Bovine lactoferrin (bLf), when evaluated for its anti-cancer effect in stomach cancer cell line (SGC-7901) showed apoptosis induction through downregulation of the AKT pathway. Finally, Lactoferricin B, a derivative of lactoferrin, has also been shown to induce ROS-dependent apoptosis induction in human leukemia cell lines and different cancer models (Xu et al., 2010).

 

Inhibition of metastasis
Lactoferrin has been reported to inhibit cell invasion and migration in various models of cancer but the exact molecular mechanism of its anti-invasive and anti-migratory activities is not cleared yet. Bovine lactoferrin showed a reversal of the EMT process in recent investigations on oral cancer cells and glioblastoma (Cutone et al., 2020).
Besides anti-migration and anti-invasiveness effects, lactoferrin has been also reported to suppress metastasis of cancer. Particularly, when the apo form of bovine lactoferrin was injected subcutaneously in mice with lymphoma and melanoma cells, it inhibits the liver, lung, and spleen cancer metastasis along with inhibition of tumor-induced angiogenesis. Moreover, the oral administration of bovine lactoferrin and lactoferricin B to mice having highly metastatic colon cancer suppresses the metastasis in the lunginhibitingt colony formation. A recent study demonstrated that a deficiency of lactoferrin increased cancer metastasis to the lungs through recruiting myeloid suppressor cells in lactoferrin knockout mice. Hence, lactoferrin is an important agent for controlling the metastatic behavior of cancer (Chea et al., 2018).

 

Immunomodulation effects
Inflammatory cells make up the tumour microenvironment which is a very important factor in tumour metastasis and inhibition. These inflammatory cells that participate in the tumor microenvironment are mainly leukocytes including macrophages, dendritic cells, lymphocytes, and neutrophils. These cells secrete various inflammatory mediators, cytotoxic molecules, and cell-killing soluble mediators to regulate cancer progression. Tumour fate is usually decided by the interplay between immunity and cancer regulation (Qu et al., 2018). Therefore, immunomodulation has a great impact on cancer biology and in this case, the molecules that boost cytotoxic components of immunity can be good candidates as an adjuvant to chemotherapeutic agents.
Lactoferrin has been proven to potentiate components of adaptive immunity and has anti-inflammatory activity. Both bovine and human lactoferrin are reported to enter in host cell nucleus and can bind with DNA to modulate gene expression thus, controlling inflammation and regulating carcinoma. In another study, bovine lactoferrin inhibited tumor growth in human lung cancer cells and murine models by regulating the levels of vascular endothelial growth factor. Finally, bLF is shown to provide a shield against iron disorders that lead to cancer by immunomodulation and by decreasing levels of pro-inflammatory cytokines such as tumor necrosis factor and Interleukin (Lepanto et al., 2019).

 

Lactoferrin and breast cancer
The potential of bovine lactoferrin has been assessed in various models of breast cancer. Duarte et al. studied the effect of bovine milk lactoferrin on two HS578T and T47D cancer cell lines of human breast cancer. The cells were given exposure or treated with different concentrations of lactoferrin ranging from 0.125 to 125μM. Thus, milk lactoferrin is proven to be a suitable anti-cancerous agent against breast cancer (Gibbons et al., 2015).

 

Lactoferrin and colorectal cancer
Bovine Lactoferrin and its peptide derivative Lactoferricin B (LFcinB) have been evaluated for their anti-cancer activity against colorectal cancer cells. It has been believed that bLF and LFcinB applied their anti-cancerous activity by regulating multiple signaling pathways.
The oral administration of lactoferrin from bovine milk was known to have anti-cancer effects on colorectal cancer so, a randomized controlled trial study was directed to assess the effect of bovine lactoferrin on the growth of colorectal polyps when administered orally.
Camel’s milk lactoferrin significantly reduced the proliferation of colorectal cancer cells and prevented DNA damage (Jiang et al., 2017).

 

Lactoferrin and prostate cancer
Lactoferrin which possesses anti-cancerous and anti-metastatic activity was evaluated for its potential to manage prostate cancer. The cells were treated with bLF and the rate of cell proliferation, intracellular pH, apoptosis, and extracellular acidification was analyzed. These experiments showed that lactoferrin from milk sources can be used to manage prostate cancer and its metastasis (Zadvornyi et al., 2018).

 

Lactoferrin as a carrier for drug delivery in cancer
Moreover, untargeted delivery of chemotherapeutic agents is one of the main contributing factors for multi-drug resistance in cancer. Therefore, specific targeting of cancer cells in cancer therapy is highly desirable. Many ligands and particles have been evaluated for specific targeting of cancer cells including antibodies, organic molecules, Nanoparticles, and Lactoferrin (Bazak et al., 2015). Lactoferrin has been shown to conjugate with nanoparticles loaded with anti-cancerous drugs for specific targeting of cancer cells and interestingly, Lactoferrin itself can act as a carrier for targeted delivery of anti-cancerous drugs.
Doxorubicin (Dox), an anti-cancerous drug used in chemotherapy, has been evaluated in conjugation with Bovine lactoferrin to enhance its working and internalization in prostate cancer cell lines and then in mice models.
Lactoferrin can cross the blood-brain barrier and possess a good safety profile. Lactoferrin-derived nanoparticles loaded with different anti-cancer agents are shown to be safe, having increased permeation to the blood-brain barrier, and are efficient in the delivery of chemotherapeutic agents to glioma cells (Li et al., 2018).

 

Conclusion
Lactoferrin from bovine milk has emerged as a suitable protein for cancer treatment because of its biological activities and provides a more stable treatment. Bovine lactoferrin is known to exert its anti-cancerous potential in different types of cancers through its different extracellular and intracellular effects. Moreover, bLF can cross blood blood-brain barrier which makes it useable for tumors in the brain. Lastly, bLF has emerged as a potential carrier for the targeted delivery of chemotherapeutics specifically thee ic killing of cancer cells.

 

References

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