Lactoferrin Exerts Antitumor Effects by Inhibiting Angiogenesis in a HT29 Human Colon Tumor Model

Abstract

To investigate the effect and potential mechanisms of lactoferrin on colon cancer cells and tumors, HT29 and HCT8 cells were exposed to varying concentrations of lactoferrin, and the impacts on cell proliferation, migration, and invasion were observed. Cell proliferation test showed that high dosage of lactoferrin (5-100 mg/mL) inhibited cell viability in a dose-dependent manner, with the 50% concentration of inhibition at 81.3 ± 16.7 mg/mL and 101 ± 23.8 mg/mL for HT29 and HCT8 cells, respectively. Interestingly, migration and invasion of the cells were inhibited dramatically by 20 mg/mL lactoferrin, consistent with the significant down regulation of VEGFR2, VEGFA, pPI3K, pAkt, and pErk1/2 proteins. HT29 was chosen as the sensitive cell line to construct a tumor-bearing nude mice model. Notably, HT29 tumor weight was greatly reduced in both the lactoferrin group (26.5 ± 6.7 mg) and the lactoferrin/5-Fu group (14.5 ± 5.1 mg), compared with the control one (39.3 ± 6.5 mg), indicating that lactoferrin functioned as a tumor growth inhibitor. Considering lactoferrin also reduced the growth of blood vessels and the degree of malignancy, we concluded that HT29 tumors were effectively suppressed by lactoferrin, which might be achieved by regulation of phosphorylation from various kinases and activation of the VEGFR2-PI3K/Akt-Erk1/2 pathway.

Use of Nutraceuticals in Angiogenesis-Dependent Disorders

“…Milk contains at least three proteins with modulatory effect on angiogenesis [ 51 ]. The antiangiogenic activity of milk lactoferrin, known from 1997, has been confirmed recently in experimental human colon cancer models, consistent with a significant downregulation of VEGFR2, VEGF-A, pPI-3K, pAkt, and pERK1/2 proteins [ 52 ].…”

Investigation and comparison of the anti-tumor activities of lactoferrin, α-lactalbumin, and β-lactoglobulin in A549, HT29, HepG2, and MDA231-LM2 tumor models

“…In several studies, LF was proven to inhibit the growth of colon cancer, liver cancer, lung cancer, and breast cancer through inducing tumor cell apoptosis. Li et al (2017) reported that iron-saturated LF sample inhibited the growth and metastasis of HT29 tumor, mainly through inhibiting the VEGFR2-VEGFA-PI3K-Akt angiogenesis pathway. In the Morishita et al (2015) hepatocarcinoma cell model, LF attenuated fatty acid-induced lipotoxicity via Akt signaling.…”

Lactoferrin Induces the Synthesis of Vitamin B6 and Protects HUVEC Functions by Activating PDXP and the PI3K/AKT/ERK1/2 Pathway

“…Lactoferrin (80 kDa) belongs to the iron-binding protein family. It contains more than 700 amino-acid residues and exists in several biological secretions, including tears, saliva, and milk, and in the secondary granules of granulocytes [1,2]. Lactoferrin is divided into three types according to the degree of iron (Fe) saturation: the holo-type (with two iron atoms), single iron type (with one iron atom), and apo-type (with no iron atom).…”

“…Lactoferrin is divided into three types according to the degree of iron (Fe) saturation: the holo-type (with two iron atoms), single iron type (with one iron atom), and apo-type (with no iron atom). The expression levels of lactoferrin in human milk are much higher than in other mammals, and its concentration in human milk decreases over the months of lactation [1,2]. In recent years, multiple studies of the biological activities of lactoferrin have shown that it has many beneficial effects on living organisms, including antioxidant, antiviral, anti-inflammatory, antitumor, antibiosis, and antiparasitic effects [2,3,4,5].…”

“…The expression levels of lactoferrin in human milk are much higher than in other mammals, and its concentration in human milk decreases over the months of lactation [1,2]. In recent years, multiple studies of the biological activities of lactoferrin have shown that it has many beneficial effects on living organisms, including antioxidant, antiviral, anti-inflammatory, antitumor, antibiosis, and antiparasitic effects [2,3,4,5]. Lactoferrin is also reported to strengthen the immune system, protect the cardiovascular system, reduce gastrointestinal stimulation, improve sleep quality, affect the metabolism of elemental Fe, and balance the concentration of Fe in an organism [6,7,8,9,10].…”