Abstract
Originally known as host defence peptides for their substantial bacteriotoxic effects, many cationic antimicrobial peptides also exhibit a potent cytotoxic activity against cancer cells. Their mode of action is characterized mostly by electrostatic interactions with the plasma membrane, leading to membrane disruption and rapid necrotic cell death. In this work, we have designed a novel cationic peptide of 27 amino acids (Cypep-1), which shows efficacy against a number of cancer cell types, both in vitro and in vivo, while normal human fibroblasts were significantly less affected. Surface plasmon resonance experiments as well as liposome leakage assays monitored by fluorescence spectroscopy revealed a substantial binding affinity of Cypep-1 to negatively charged liposomes and induced significant leakage of liposome content after exposure to the peptide. The observed membranolytic effect of Cypep-1 was confirmed by scanning electron microscopy (SEM) as well as by time-lapse confocal microscopy. Pharmacokinetic profiling of Cypep-1 in rats showed a short plasma half-life after i.v. injection, followed mainly by retention in the liver, spleen and kidneys. Extremely low concentrations within the organs of the central nervous system indicated that Cypep-1 did not pass the blood-brain-barrier. Local treatment of 4T1 murine mammary carcinoma allografts by means of a single local bolus injection of Cypep-1 led to a significant reduction of tumour growth in the following weeks and prolonged survival. Detailed histological analysis of the treated tumours revealed large areas of necrosis. In sum, our findings show that the novel cationic peptide Cypep-1 displays a strong cytolytic activity against cancer cells both in vitro and in vivo and thus holds a substantial therapeutic potential.
Highlights
Occurring antimicrobial peptides (AMPs) represent a first-line defence of eukaryotic cells against bacteria, protozoa, fungi and viruses [1,2,3]
Known as host defence peptides [4] or defensines [5], many AMPs, as well as their synthetic variants, have been found to exert a broad spectrum of antimicrobial and anticancer effects, while often affecting normal mammalian cells to a far lesser extent [6,7,8,9,10,11,12,13,14]. These cytolytic effects of AMPs are largely www.impactjournals.com/Genes & Cancer attributed to their cationic nature [15, 16], leading to electrostatic interactions with negatively charged cell membranes [17]
This showed that the monolayer of a U87 cell line had contracted considerably after 3 hours exposure and extensive cell loss was observed
Summary
Occurring antimicrobial peptides (AMPs) represent a first-line defence of eukaryotic cells against bacteria, protozoa, fungi and viruses [1,2,3]. Known as host defence peptides [4] or defensines [5], many AMPs, as well as their synthetic variants, have been found to exert a broad spectrum of antimicrobial and anticancer effects, while often affecting normal mammalian cells to a far lesser extent [6,7,8,9,10,11,12,13,14] These cytolytic effects of AMPs are largely www.impactjournals.com/Genes & Cancer attributed to their cationic nature [15, 16], leading to electrostatic interactions with negatively charged cell membranes [17]. Since their lytic potential is neither receptor-mediated nor dependent on the cellular replication cycle, AMPs targets multi-drug-resistant cancer cells successfully and represent a promising group of novel oncolytic treatment agents [12, 19, 22,23,24,25]
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