Studies on Mechanism of Action of Anticancer Peptides by Modulation of Hydrophobicity Within a Defined Structural Framework

Huang, Yibing; Wang, Xiaofei; Wang, Hong-ye; Liu, Yu; Chen, Yuxin

doi:10.1158/1535-7163.mct-10-0811

Cited by 173 publications

(146 citation statements)

References 24 publications

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“…14 To improve the cell specificity or therapeutic index of this peptide and its analogues, D-amino acids were introduced into the nonpolar face to modulate peptide hydrophobicity and helicity. 15 Additionally, simple terminal modifications including N-terminal acetylation, C-terminal amidation, end-tagging and single amino acid substitutions have also been employed to alter the properties of AMPs and ACPs, with some of these peptide variants showing enhanced antibacterial and anticancer activity and cell selectivity.…”

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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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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“…Among of them, peptide of A12L/ A20L showed the strongest activity against HeLa cell line. Our data's suggested that the hydrophobicity of peptide plays a crucial role in the action against cancer cells due to the necrotic-like membrane disruption mechanism [3]. In addition, helicity was systematically modulated by introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix and the therapeutic index of A12L/A20L against HeLa cells was improved by 9-fold and 22-fold, respectively [17].…”

Section: Introductionmentioning

confidence: 70%

“…For the necrosis activity, most peptides are membrane activity peptides, such as lytic peptide or derived from the antimicrobial peptides (AMPs). In the first, they can quickly bind to the highly negative charged cancer cell membrane by the electrostatic interactions, then destabilize and disrupt the integrity of cell membrane through the hydrophobic interactions leading to necrosis of cancer cells [3][4][5]. For the apoptosis activity, as we know, most tumor cells resist apoptosis due to a deregulation of pro-and anti-apoptotic proteins, however, partly ACPs can result to the releasing of cytochrome c (Cyt c) and lead to the apoptosis of cancer cells by the permeation and swelling of mitochondria membrane if ACPs internalized inside eukaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

Design and Modification of Anticancer Peptides

Hu¹,

Chen²,

Zhao³

et al. 2016

Drug Des

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Cancer is a great concern in the public health and development of novel therapeutic agent or strategy become urgently. Anticancer peptides (ACPs) have become promising anticancer drug candidate molecules due to their several extraordinary properties, such as small size, high activity, low immunogenicity, good biocompatibility, diversity of sequence and more modification sites for the functional molecules. However, the low stability and short half-life of peptides are the major barriers for the application. In this review, we focus on the methods of peptide design and modification to improve the stability, half-life time and specificity of ACPs, which including amino acid substitution, cyclization, hybridization, fragmentization, modification of C-and N-terminal of peptide by polymer or targeting molecules, etc.modification of C-and N-terminal of peptide by polymer or targeting molecules, etc. The schematic diagram of major design and modification strategies of ACPs are shown in Figure 1.

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“…Our observations are strongly supported by a previous report [11] wherein certain membrane active alphahelical peptides have been revealed to produce pores or channels and bind quickly to the surface of negatively charged HeLa cells via a strong electrostatic interaction. We hereby hypothesise that nisin being cationic in nature might be selectively toxic to the negatively charged HaCat cells thereby sparing the zwitterionic eukaryotic cells based on the fact that outer membrane of cancerous cells is negatively charged due to the presence of certain glycoproteins [21]. In addition to this, preferential facilitation of the uptake of DOX by tumor cells in presence of nisin might also help in improving the therapeutic index of this very important chemotherapeutic agent as doxorubicin is known to exert cardiotoxicity at higher doses which limits the maximum effective dose of this agent that can be used to cure cancers.…”

Section: Discussionmentioning

confidence: 99%

Nisin Augments Doxorubicin Permeabilization and Ameliorates Signaling Cascade during Skin Carcinogenesis

Preet

Satish²,

ey³

et al. 2016

Transl Med (sunnyvale)

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Research ArticleOpen Access [12]. We have also recently demonstrated an additive in vivo anti-cancer effect of nisin in conjunction with a conventional chemotherapeutic; doxorubicin (DOX) against murine skin carcinogenesis [13]. The present study further delineates the underlying mechanism of nisin-DOX additive anticancer action in vivo (in a murine model) and in vitro (using HaCaT cell lines) against skin carcinogenesis. Materials and Methods MaterialAll the chemicals used in the present study were of analytical grade and were obtained from standard companies. ELISA plates, tissue culture plates (96 /8 well), culture dishes, Serological plates, Roux culture bottles, 0.2µm sterile syringe filters (non-pyrogenic). DMBA (7,12-Dimethylbenzylanhracene), TPA (12-O-tetradecanoylphorbol-13-acetate), RPMI 1640 (Rose Well Park Memorial Institute Lab no. 1640) (Hi-media, India), doxorubicin nisinand3-(4,5-dimethylthiazol2yl)-2,5-diphenyl tetrazolium bromide were procured from Sigma Aldrich.N-phenyl-1-napthylamine (NPN), bovine serum albumin (BSA), 5,5-dithiobis-2-nitrobenzoic acid (DTNB), thiobarbituric acid (TBA), ethanol, formaldehyde, hydrogen peroxide (H 2 O 2 ), benzene, paraffin wax, xylene, trichloroacetic acid (TCA), sodium chloride (NaCl), EDTA, Folin's Reagent, sodium carbonate, copper sulphate, AbstractBackground: Multidrug resistance exhibited by cancerous cells has proved to be a big hurdle in the development of an effective anti-cancer therapy. We previously demonstrated nisin-doxorubicin adjunct therapy to exhibit strong additive anti-cancer effect against DMBA -induced murine skin carcinogenesis but the mechanism remained unexplored. Methods:The in vivo tumoricidal activity of the combination was validated in terms of animal bioassay observations while ex vivo anti-cancer effect was monitored by employing HaCat cell lines. Results:The combination was found to be additive in vivo as evidenced by larger decreases in mean tumor burden and tumor volumes. The IC 50 values of nisin and DOX alone were evaluated to be 16 µg/ml and 4 µg/ml respectively while the sub-inhibitory concentration of DOX was reduced to 2 µg/ml when nisin was used as an adjunct. Q values calculated using MTT assays indicated the combination to be synergetic than additive. The mechanism was found to involve enhanced membrane permeabilization as well as reduced expression of NF-Κb, TNF-α, TNF-β, IL-1 and IL-6. Conclusion:As combined effect of nisin and DOX even at halved concentrations was significantly higher than either drug alone, these observations might help in lowering the chemotherapeutic doses of DOX thereby decreasing its associated side effects.

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Studies on Mechanism of Action of Anticancer Peptides by Modulation of Hydrophobicity Within a Defined Structural Framework

Cited by 173 publications

References 24 publications

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

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

Design and Modification of Anticancer Peptides

Nisin Augments Doxorubicin Permeabilization and Ameliorates Signaling Cascade during Skin Carcinogenesis

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