Abstract
Host defense peptides (HDP) constitute effector molecules of the innate immune system. Besides acting against microbia and fungi, they exhibit broad and selective oncolytic activity. The underlying mechanism is at least partially attributable to elevated surface-exposed levels of phosphatidylserine (PS) on tumor targets. In this study, comprehensive analysis of NK-2-based derivatives (C7A, C7A-D21K, and C7A-Δ) was done on patient-derived ultra-low passage colorectal carcinoma (CRC) cell lines. Peptides were designed to improve antitumoral potential. Mellitin was used as positive control and a non-toxic peptide (NK11) served as negative control. Subsequently, effectiveness of local HDP application was determined in xenopatients. Generally, CRC lines displayed a heterogeneous pattern of surface-exposed PS, which was usually below standard CRC cells. Of note, five out of seven cell lines were susceptible towards HDP-mediated lysis (lytic activity of peptides: C7A-D21K > C7A-Δ= C7A). Oncolytic activity correlated mostly with surface-exposed PS levels. Apoptosis as well as necrosis were involved in killing. In an in vivo experiment, substantial growth inhibition of HROC24 xenografts was observed after HDP therapy and, surprisingly, also after NK11 treatment. These promising data underline the high potential of HDPs for oncolytic therapies and may provide a rationale for optimizing preclinical treatment schedules based on NK-2.
Highlights
Antimicrobial peptides, referred to as Host defense peptides (HDP), have originally been identified as an alternative weapon against bacterial infections
Peptides (C7A, C7A-D21K, C7A-Δ), and NK11 used in this study were based on NK-2 (Table 2 and [17])
HDPs applied in this study were based on NK-2, a porcine immune cell-derived peptide, whose selective killing of different human cancer lines is well established [10]
Summary
Antimicrobial peptides, referred to as Host defense peptides (HDP), have originally been identified as an alternative weapon against bacterial infections. This is important, as clinical handling of multiresistant bacterial variants is increasingly difficult. These peptides represent an ancient yet very effective part of the innate immune system as first line of defense against invading bacteria. HDPs exhibit a unique mode of action Due to their cationic amphipathic nature they preferentially bind to negatively charged membranes [3,4,5] – a common characteristic of bacterial membranes, making them a perfect HDP target. These cationic peptides directly interact with the target cells’ lipid matrix instead of a specific enzyme or receptor
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