Bovine Milk Lactoferrin Selectively Kills Highly Metastatic Prostate Cancer PC-3 and Osteosarcoma MG-63 Cells In Vitro

Abstract

Prostate cancer and osteosarcoma are the second most common type of cancer affecting men and the fifth most common malignancy among adolescents, respectively. The use of non-toxic natural or natural-derived products has been one of the current strategies for cancer therapy, owing to the reduced risks of induced-chemoresistance development and the absence of secondary effects. In this perspective, lactoferrin (Lf), a natural protein derived from milk, emerges as a promising anticancer agent due to its well-recognized cytotoxicity and anti-metastatic activity. Here, we aimed to ascertain the potential activity of bovine Lf (bLf) against highly metastatic cancer cells. The bLf effect on prostate PC-3 and osteosarcoma MG-63 cell lines, both displaying plasmalemmal V-ATPase, was studied and compared with the breast cancer MDA-MB-231 and the non-tumorigenic BJ-5ta cell lines. Cell proliferation, cell death, intracellular pH, lysosomal acidification, and extracellular acidification rate were evaluated. Results show that bLf inhibits proliferation, induces apoptosis, intracellular acidification, and perturbs lysosomal acidification only in highly metastatic cancer cell lines. By contrast, BJ-5ta cells are insensitive to bLf. Overall, our results establish a common mechanism of action of bLf against highly metastatic cancer cells exhibiting plasmalemmal V-ATPase. This study opens promising perspectives for further research on the anticancer role of Lf, which ultimately will contribute to its safer and more rational application in the human therapy of these life-threatening cancers.

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

“…Except for the indirect immunomodulatory pathway, the other mechanisms require the direct recognition of and selection between cancerous and normal cells by Lf, possibly involving a primary interaction with peculiar cancer cell surface receptors or a secondary one via the regulation of differential intracellular networks. To date, only few evidences have been reported for the primary recognition between Lf and cancer cell surface receptors [120][121][122]. In this respect, most of cancerous cells have a high content of proteoglycans, glycosaminoglycans (GAGs, mainly heparan and chondroitin sulfates), as well as of sialic acids, all these molecules being well-known interactors for Lfs [120,123,124].…”

“…Recently, the vacuolar H + -ATPase (V-H + -ATPase) was described as a potential target for bLf in highly metastatic breast cancer cell lines [121,122]. BLf was found to induce apoptosis, along with a significant decrease in V-H + -ATPase-mediated extracellular acidification rate, in two highly metastatic breast cancer cell lines, Hs 578T and MDA-MB-231, displaying a prominent localization of V-H + -ATPase at the plasma membrane, but not in the lowly metastatic T-47D or in the non-tumorigenic MCF-10-2A cell lines [121].…”

“…BLf was found to induce apoptosis, along with a significant decrease in V-H + -ATPase-mediated extracellular acidification rate, in two highly metastatic breast cancer cell lines, Hs 578T and MDA-MB-231, displaying a prominent localization of V-H + -ATPase at the plasma membrane, but not in the lowly metastatic T-47D or in the non-tumorigenic MCF-10-2A cell lines [121]. By a similar approach, bLf was described to selectively act as pro-apoptotic agent on highly metastatic prostate PC-3 and osteosarcoma MG-63 cell lines, both displaying aberrant plasma membrane localization of V-H + -ATPase [122]. Again, non-tumorigenic BJ-5ta cell line did not show sensitivity to bLf treatment.…”

The Nonapeptide RWQWRWQWR: A Promising Molecule for Breast Cancer Therapy

“…Furthermore, it has been described that the cytotoxic effect of LfcinB is related to the apoptosis mechanisms in other human cancer cell lines, such as stomach (SGC-7901), pheochromocytoma (PC12), breast (MDA-MB-435, MCF-7, HS578T and T-47D), and leukemia (Jurkat). [13,26,[34][35][36][37][38] LfcinB (21)(22)(23)(24)(25) Pal generated a significant increase in mitochondrial membrane depolarization, in a manner similar to the tetrameric peptide, which induced 18% mitochondrial membrane depolarization events, indicating that the cytotoxic effect of these peptides against MCF-7 could be mediated by the intrinsic apoptotic pathway. [18] In breast cancer cell line MDA-MB-435, when treated with LfcinB, cytotoxicity caused mainly by apoptotic events determined by DNA fragmentation, chromatin condensation, and nuclear fragmentation was also observed.…”

Lactoferrin (LF): a natural antimicrobial protein

“…[29] This protein has amino acids with the highest contents including alanine, leucine, glycine, tryptophan, histidine and methionine with 10%, 9%, 7%, 1.5%, 1.3% and 0.6% respectively. [30][31][32] Current uses of bovine lactoferrin include dietary iron supplements, infant formulas, beverages, chewing gums, fermented milk and milk products, cosmetic formulas, immune-enhancing nutraceuticals, feed and pet care supplements. It inhibits bacterial adhesion on abiotic surfaces.…”