Lactoferrin's Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action

Abstract

Despite recent advances in cancer therapy, current treatments, including radiotherapy, chemotherapy, and immunotherapy, although beneficial, present attendant side effects and long-term sequelae, usually more or less affecting quality of life of the patients. Indeed, except for most of the immunotherapeutic agents, the complete lack of selectivity between normal and cancer cells for radio- and chemotherapy can make them potential antagonists of the host anti-cancer self-defense over time. Recently, the use of nutraceuticals as natural compounds corroborating anti-cancer standard therapy is emerging as a promising tool for their relative abundance, bioavailability, safety, low-cost effectiveness, and immuno-compatibility with the host. In this review, we outlined the anti-cancer properties of Lactoferrin (Lf), an iron-binding glycoprotein of the innate immune defense. Lf shows high bioavailability after oral administration, high selectivity toward cancer cells, and a wide range of molecular targets controlling tumor proliferation, survival, migration, invasion, and metastasization. Of note, Lf is able to promote or inhibit cell proliferation and migration depending on whether it acts upon normal or cancerous cells, respectively. Importantly, Lf administration is highly tolerated and does not present significant adverse effects. Moreover, Lf can prevent development or inhibit cancer growth by boosting adaptive immune response. Finally, Lf was recently found to be an ideal carrier for chemotherapeutics, even for the treatment of brain tumors due to its ability to cross the blood-brain barrier, thus globally appearing as a promising tool for cancer prevention and treatment, especially in combination therapies.

Keywords: apoptosis; cancer; cancer targeting; epithelial to mesenchymal transition; lactoferrin; lactoferrin bioavailability; metastasis; tumor proliferation.

Figure 1

Side (A,B) and top (C,D) views of the crystal structures of diferric human lactoferrin (hLf) (A,C) (PDB code = 1B0L) and bovine lactoferrin (bLf) (B,D) (PDB code = 1BLF). The N-lobe is highlighted in orange and the C-lobe in cyan, the connecting α-helix (aa. 334–344 for both glycoproteins) in violet, and the ferric irons are depicted as black spheres. The lactoferricin (aa. 1–47 in hLf and 17–41 in bLf) and lactoferrampin (aa. 269–285 in hLf and 268–284 in bLf) regions are highlighted in blue and green, respectively. N-terminal regions, able to interact with different glycosaminoglycans on cancer cells, are depicted in red and correspond to the first five amino acids (G¹RRRR⁵) for hLf, while in bLf only Asn in position 5 (N⁵) is shown, as the first four amino acids (A¹PRK) are absent in the crystal structure. As evident from the top view, the cationic lactoferricin, lactoferrampin and the N-terminal region are packed close to each other and constitute a basic domain able to interact with prokaryotic and eukaryotic cell surface receptors, thus exerting multifaceted activities.

Figure 2

Schematic representation of bovine Lactoferrin (bLf) efficiency in counteracting migration and invasion by reverting epithelial-to-mesenchymal transition (EMT) process in cancer cells. (A) Mesenchymal phenotype, characterized by a spindle-like shape, presents high levels of vimentin and Snail/Twist (S/T), down-regulation of cadherins’ expression and p-STAT3-activation by interleukin (IL)-6. All these factors let the cell to acquire an invasive phenotype able to detach from the primary site and invade surrounding tissues and blood vessels. (B) Epithelial phenotype upon bLf treatment, which is able to revert EMT by its multi-targeting activity. After LRP1-mediated uptake and nuclear localization, bLf down-regulates vimentin, Snail and Twist expression, thus increasing cadherins’ levels. Moreover, bLf inhibits IL-6-mediated STAT3 activation.