Identification of Unprecedented Anticancer Properties of High Molecular Weight Biomacromolecular Complex Containing Bovine Lactoferrin (HMW-bLf)

Abstract

With the successful clinical trials, multifunctional glycoprotein bovine lactoferrin is gaining attention as a safe nutraceutical and biologic drug targeting cancer, chronic-inflammatory, viral and microbial diseases. Interestingly, recent findings that human lactoferrin oligomerizes under simulated physiological conditions signify the possible role of oligomerization in the multifunctional activities of lactoferrin molecule during infections and in disease targeting signaling pathways. Here we report the purification and physicochemical characterization of high molecular weight biomacromolecular complex containing bovine lactoferrin (≥250 kDa), from bovine colostrum, a naturally enriched source of lactoferrin. It showed structural similarities to native monomeric iron free (Apo) lactoferrin (∼78–80 kDa), retained anti-bovine lactoferrin antibody specific binding and displayed potential receptor binding properties when tested for cellular internalization. It further displayed higher thermal stability and better resistance to gut enzyme digestion than native bLf monomer. High molecular weight bovine lactoferrin was functionally bioactive and inhibited significantly the cell proliferation (p<0.01) of human breast and colon carcinoma derived cells. It induced significantly higher cancer cell death (apoptosis) and cytotoxicity in a dose-dependent manner in cancer cells than the normal intestinal cells. Upon cellular internalization, it led to the up-regulation of caspase-3 expression and degradation of actin. In order to identify the cutting edge future potential of this bio-macromolecule in medicine over the monomer, its in-depth structural and functional properties need to be investigated further.

Upregulation of sodium iodide symporter (NIS) protein expression by an innate immunity component: Promising potential for targeting radiosensitive retinoblastoma

“…The multifunctional effects of Lf molecule have been suggested to depend on its target cells and on the presence of specific receptors (Ebrahim et al 2014;Jiang et al 2011;Kanwar & Kanwar 2013). This was indeed observed in the current study, where the absence of TfR mRNA might be responsible for the comparatively lower uptake in Weri-Rb-1 cells than Y79 cells.…”

“…Due to its iron binding properties, Native bLf is approximately 15-20 % saturated, and it can be modified to forms with different levels of iron: Apo-bLf (< 5% iron saturation) and Holo-bLf (100 % iron saturated). With the successful clinical trials, multifunctional glycoprotein bLf is gaining attention as a safe nutraceutical and biologic drug targeting cancer, chronicinflammatory, viral and microbial diseases (Ebrahim et al 2014; EFSA Panel on Dietetic Products 2012; Rulis 2001; Tsuda et al 2010) Lf is also thought to act as a transcriptional activator once it binds to the nucleus (He & Furmanski 1995). Another transcriptional activity of Lf was shown in increasing gene expression of IL-1β (Son KN et al 2002) and TGF-β1 (Liao, Jiang & Lönnerdal 2012).…”

Biodegradable Eri silk nanoparticles as a delivery vehicle for bovine lactoferrin against MDA-MB-231 and MCF-7 breast cancer cells

“…A previous study from our laboratory has shown that bLf forms are prone to Omnizyme degradation; however, upon degradation, they give rise to a large C-lobe fragment (51 kDa), a small N-lobe fragment (36 kDa), and product fragments of non-homologous cleavage (~kDa). 46 Similar findings were observed in the present study, confirming that our findings are in accordance with the published reports.…”

Evaluation of Milk Colostrum Derived Lactoferrin of Sahiwal (Bos indicus) and Karan Fries (Cross-Bred) Cows for Its Anti-Cancerous Potential

“…Interestingly, in the present investigation, the commercially available Lf showed highest anti-cancer activity than the two Lfs purified in the laboratory using SAC and KFC colostrum. Recently, few reports have also indicated the difference in anti-cancer efficacy of iron saturated and unsaturated forms of Lf [19,38,39]. Some of the previous studies have suggested that the effect of Lf on cellular parameters might depend upon its extent of iron saturation.…”