Anticancer activity of bovine lactoferricin and a cytolytic 9-mer peptide : from milk to cancer vaccine?

Abstract

Cationic antimicrobial peptides (CAPs) are found in many diverse species playing a part in the innate immune system. CAPs are important as antimicrobial agents in most organisms, being able to kill a wide range of bacteria as well as fungi, enveloped viruses and protozoa. Certain CAPs also exhibit direct cytotoxic activity against many different types of human cancer cells. Bovine lactoferricin (LfcinB) derived from the protein bovine lactoferrin found in cow milk has been the starting point for this thesis. LfcinB is a CAP which exhibits antimicrobial and antitumor activities. In the present work the main focus has been to explore the anticancer activity of LfcinB and the de novo designed peptide, LTX-302, which is a 9-mer cytolytic peptide optimalized from parental LfcinB. <br>We found that LfcinB kill cancer cells by necrosis due to a dual mechanism of the peptide on both the mitochondrial membranes and the plasma membranes. In vivo studies of the more active peptide, LTX-302, demonstrated a vaccinating effect against the murine A20 B-cell lymphoma in immunocompetent mice. Subcutaneously established tumors were treated with LTX-302 by intratumoral injection of the peptide and a majority of the tumors obtained complete regression upon LTX-302 treatment. The cured mice were found to be protected against a rechallenge with A20 cells, but not against Meth A sarcoma cells, indicating a specific immune response. The complete regression was T-cell dependent, and both CD4 and CD8 T-cells were required for the protection. These studies show that local treatment of cancer by a CAP can induce active immunization against the cancer, conferring a novel strategy for therapeutic vaccination against cancer.