Membrane-active host defense peptides – Challenges and perspectives for the development of novel anticancer drugs

Riedl, Sabrina; Zweytick, Dagmar; Lohner, Karl

doi:10.1016/j.chemphyslip.2011.09.004

Cited by 374 publications

(399 citation statements)

References 190 publications

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“…Cationic antimicrobial peptides (CAPs) are a class of small (o5 kDa) positively charged innate defense molecules that act primarily to destabilize or penetrate the membrane of microbial cells, in some cases via interactions with specific phospholipids 47,48 (functioning as phospholipid detectors). Interestingly, CAPs originated from different species including plants, insects, amphibians, mammals have been shown to possess antiproliferative activity towards mammalian tumor cells both in vitro and in vivo (reviewed in detail by Riedl et al 49 ). It has been suggested that increased expression of sialic acid-rich mucins 50,51 and heparan sulfate glycosaminoglycans, 52 as well as the exposure of anionic phospholipids such as PS 32,53 on the surface of tumor cells, are likely to contribute to the selectivity of these CAPs towards tumor cells.…”

Section: Alteration Of the Phospholipid Code During Tumor Progressionmentioning

confidence: 99%

“…As mentioned above, certain CAPs can kill tumor cells by permeabilizing the cell membrane. 49 Recently, it was demonstrated that the plant defensin NaD1, a CAP isolated from the ornamental tobacco Nicotiana alata, can selectively induce membrane lysis (primary necrosis) of mammalian tumor cells through binding PI(4,5)P 2 at the inner leaflet of the plasma membrane at low micromolar concentrations. 69 Although how NaD1 enters the tumor cell and gains access to the intracellular phospholipid code is unclear, the ability of NaD1 to form a multimeric complex with the phosphatidylinositol head group of PI(4,5)P 2 suggests the possibility of NaD1 acting as a phospholipid detector that can mask the cellular function of PI(4,5)P 2 , discussed further below.…”

Section: Alteration Of the Phospholipid Code During Tumor Progressionmentioning

confidence: 99%

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The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

2015

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A significant effort is made by the cell to maintain certain phospholipids at specific sites. It is well described that proteins involved in intracellular signaling can be targeted to the plasma membrane and organelles through phospholipid-binding domains. Thus, the accumulation of a specific combination of phospholipids, denoted here as the 'phospholipid code', is key in initiating cellular processes. Interestingly, a variety of extracellular proteins and pathogen-derived proteins can also recognize or modify phospholipids to facilitate the recognition of dying cells, tumorigenesis and host-microbe interactions. In this article, we discuss the importance of the phospholipid code in a range of physiological and pathological processes.

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Section: Alteration Of the Phospholipid Code During Tumor Progressionmentioning

confidence: 99%

Section: Alteration Of the Phospholipid Code During Tumor Progressionmentioning

confidence: 99%

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

2015

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“…Recent studies have reported the effective inhibition of cancer cell growth by amphipathic antimicrobial peptides (AMPs) via selectively disrupting cell membranes. [1][2][3][4] AMPs that also show anticancer activities are called anticancer peptides (ACPs). Although ACPs exhibit many desirable properties such as broad spectrum activity, high structural stability and low probability of inducing resistance, [3][4][5] their development as novel anticancer agents is hampered by their poor bioavailability, potential immunogenicity, cytotoxicity to host cells and high production costs.…”

Section: Introductionmentioning

confidence: 99%

Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

Chen

Yang

Zhao

et al. 2016

ACS Appl. Mater. Interfaces

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G(IIKK) 3 I-NH 2 (G3) has been recently shown to be highly effective at killing bacteria and inhibiting tumor cell growth while remaining benign to normal host mammalian cells.The aim of this work is to evaluate how residue substitutions of Ala (A), Val (V), Glu (E), and Lys (K) for the N-terminal Gly (G) or C-terminal Ile (I) of G3 affect the physiochemical properties and bioactivity of the variants. All substitutions caused the reduction of peptide hydrophobicity whilst N-terminal substitutions had less noticeable effect on the surface activity and helix-forming ability than C-terminal substitutions.N-terminal variants held potent antitumor activity but exhibited much lower hemolytic activity; these actions were related to the maintenance of their moderate surface pressures (12 to 16 mN/m) whilst their hydrophobicity was reduced. Thus, N-terminal substitutions enhanced the cell selectivity of the mutants relative to the control peptide G3. In contrast, C-terminal variants exhibited lower antitumor activity and further reduced hemolytic activity except for G(IIKK) 3 V-NH 2 . These features were also correlated well with their lower surface pressures (≤10 mN/m) and further decreased hydrophobicity. In spite of its very low helical content, the C-terminal variant G(IIKK) 3 V-NH 2 still displayed potent antitumor activity whilst retaining high hemolytic activity as well, again correlating well with its relatively high surface pressure and hydrophobicity. These results together indicated that surface activity governs the antitumor activity of the peptides but relative hydrophobicity influences their hemolytic activity. In contrast, helicity appears to be poorly correlated to their bioactivity. This work has demonstrated that N-terminal modifications provide a useful strategy to optimize the antitumor activity of helical anticancer peptides (ACPs) against its potential toxicity to mammalian host cells.

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“…In the case of Cr-ACP1 and Cn-AMP2, the millimolar levels of these peptides required to elicit an anticancer response is obviously prohibitive to such use. However, it has been observed that AHDPs such as Cn-AMP2 that are devoid of cationic residues possess an advantage over CHDPs with anticancer action whose possession of lysine and arginine residues makes them highly susceptible to degradation by human proteases [94,95]. This suggests that the intrinsic properties of Cr-ACP1 and similar AHDPs, such as cycloviolacin Y4 and cycloviolacin O24, which also lack cationic residues, may endow them with anticancer mechanisms that are not available to their cationic counterparts making them attractive propositions as candidates for therapeutic development.…”

Section: Discussionmentioning

confidence: 99%

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

Harris¹,

Prabhu²,

Dennison³

et al. 2016

PPL

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Abstract:It is becoming increasingly clear that plants ranging across the plant kingdom produce anionic host defence peptides (AHDPs) with potent activity against a wide variety of human cancers cells. In general, this activity involves membrane partitioning by AHDPs, which leads to membranolysis and / or internalization to attack intracellular targets such as DNA. Several models have been proposed to describe these events including: the toroidal pore and Shai-Matsuzaki-Huang mechanisms but, in general, the mechanisms underpinning the membrane interactions and anticancer activity of these peptides are poorly understood. Plant AHDPs with anticancer activity can be conveniently discussed with reference to two groups: cyclotides, which possess cyclic molecules stabilized by cysteine knot motifs, and other ADHPs that adopt extended andhelical conformations. Here, we review research into the anticancer action of these two groups of peptides along with current understanding of the mechanisms underpinning this action.

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Membrane-active host defense peptides – Challenges and perspectives for the development of novel anticancer drugs

Cited by 374 publications

References 190 publications

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

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