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.
Highlights
Cancer is currently one the most lethal diseases worldwide, and metastases are the main cause of cancer-associated mortality
To test whether the highly metastatic prostate cancer PC-3 and the osteosarcoma MG-63 cell lines were sensitive to bovine lactoferrin (bLf), we optimized a Carboxyfluorescein diacetate succinimidyl ester (CFSE) staining protocol and used the bLf-sensitive highly metastatic breast cancer cell line MDA-MB-231 for comparison
We found that cell fluorescence 24 h after incubation with bLf, etoposide, or cisplatin—the latter used as positive controls for PC-3 and MG-63, respectively—was not significantly different from that of untreated cells (Figures 1A,B)
Summary
Cancer is currently one the most lethal diseases worldwide, and metastases are the main cause of cancer-associated mortality. Lactoferrin (Lf) is a natural ironbinding glycoprotein that was first identified in bovine milk It is synthesized by mucosal epithelial cells and neutrophils during inflammatory processes and is present in many tissues and body fluids of mammals. Lf from bovine milk [bovine lactoferrin (bLf)], which exhibits the same biological properties as the human Lf, is cheaply produced compared with other sources but is commercially available and well tolerated after ingestion [11]. These properties confer to bLf the requirements of an ideal nutraceutical. Orally administered recombinant human Lf was well tolerated and displayed anticancer activity against solid tumors like non-small cell lung cancer and renal cell carcinoma, without secondary effects [13, 14]
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