Identification of a novel lytic peptide for the treatment of solid tumours

Abstract

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.

Improved Drug Delivery to Brain Metastases by Peptide-Mediated Permeabilization of the Blood–Brain Barrier

“…Taken together with data presented in Supplementary Figs. S2 and S3, this indicates that cell lysis is likely involved especially at higher peptide concentrations, likely due to a cationic effect leading to electrostatic interactions with negatively charged cell membranes (35), in addition to the endocytosis mechanisms indicated by flow cytometry (Fig. 2).…”

LyeTx I-b Peptide Attenuates Tumor Burden and Metastasis in a Mouse 4T1 Breast Cancer Model

“…On the fifth day, the other three groups received the same treatment subcutaneously. The body weight and tumor volume were monitored every three days, and signs of distress and pain were monitored daily [ 92 ]. The measurement of tumor volume was calculated using the following equation: tumor volume (mm 3 ) = length (mm) × width 2 (mm)/2 [ 93 ].…”

Results of a randomized, placebo‐controlled, first‐in‐human trial of topical CY‐002 in patients with cutaneous warts

“…CY-002 selectively induces cell death in tumour and HPV-transformed cell lines, whilst sparing normal cells by targeting membrane charge instability. 3 The objectives of this first-in-human proof-of-concept clinical study were to explore safety, tolerability and efficacy of topical CY-002 in adults with cutaneous warts.…”

“…CY-002 selectively induces cell death in tumour and HPV-transformed cell lines, whilst sparing normal cells by targeting membrane charge instability. 3 The objectives of this first-in-human proof-of-concept clinical study were to explore safety, tolerability and efficacy of topical CY-002 in adults with cutaneous warts.This was a randomized, placebo-controlled, double-blind, single-centre Phase I trial with a clinical safety run-in. Enrolled patients were otherwise healthy, above 18 years old and had ≥1, ≥3 mm cutaneous wart on the hand.…”