Anti-tumor activities of the host-defense peptide hymenochirin-1B

Samir Attoub; Hama Arafat; Milena Mechkarska; J. Michael Conlon

doi:10.1016/j.regpep.2013.10.006

Anti-tumor activities of the host-defense peptide hymenochirin-1B

Samir Attoub, Hama Arafat, Milena Mechkarska, J. Michael Conlon

School of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

Abstract

The hymenochirins are a family of cationic, amphipathic, α-helical host-defense peptides, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Of the four hymenochirins tested, hymenochirin-1B (IKLSPETKDNLKKVLKGAIKGAIVAKMV.NH₂) shows the greatest cytotoxic potency against non-small cell lung adenocarcinoma A549 cells (LC₅₀=2.5±0.2μM), breast adenocarcinoma MDA-MB-231 cells (LC₅₀=9.0±0.3μM), colorectal adenocarcinoma HT-29 cells (LC₅₀=9.7±0.2μM), and hepatocarcinoma HepG2 cells (LC₅₀=22.5±1.4μM) with appreciably less hemolytic activity against human erythrocytes (LC₅₀=213±18μM). Structure-activity relationships were investigated by synthesizing analogs of hymenochirin-1B in which Pro⁵, Glu⁶ and Asp⁹on the hydrophilic face of the helix were replaced by one or more L-lysine or D-lysine residues. The [D9K] analog displays the greatest increase in potency against all four cell lines (up to 6fold) but hemolytic activity also increases (LC₅₀=174±12μM). The [D9k] and [E6k,D9k] analogs retain relatively high cytotoxic potency against the tumor cells (LC₅₀ in the range 2.1-21μM) but show reduced hemolytic activity (LC₅₀>300μM). The data suggest that hymenochirin-1B has therapeutic potential as a template to generate potent, non-toxic anti-cancer agents.

Original language	English
Pages (from-to)	51-56
Number of pages	6
Journal	Regulatory Peptides
Volume	187
DOIs	https://doi.org/10.1016/j.regpep.2013.10.006
Publication status	Published (in print/issue) - 10 Nov 2013

Bibliographical note

Funding Information:
This work was supported by a Faculty Support Grant and a University/National Research Foundation Grant from U.A.E. University and an award from the Terry Fox Fund for Cancer Research . The authors thank Dr. Katarina Hostanska, Department of Internal Medicine, Institute for Complementary Medicine, University Hospital of Zurich for providing the A549 cell line, Prof. Joan Massague, Howard Hughes Medical Institute, Memorial Sloan–Kettering Cancer Center for providing the MDA-MB-231 cell line, and Prof. Nico Nagelkerke, Institute of Public Health, U.A.E. University for help with data analysis.

Keywords

Anti-cancer
Frog skin
Host-defense peptide
Hymenochirin
Structure-activity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.regpep.2013.10.006

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title = "Anti-tumor activities of the host-defense peptide hymenochirin-1B",

abstract = "The hymenochirins are a family of cationic, amphipathic, α-helical host-defense peptides, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Of the four hymenochirins tested, hymenochirin-1B (IKLSPETKDNLKKVLKGAIKGAIVAKMV.NH2) shows the greatest cytotoxic potency against non-small cell lung adenocarcinoma A549 cells (LC50=2.5±0.2μM), breast adenocarcinoma MDA-MB-231 cells (LC50=9.0±0.3μM), colorectal adenocarcinoma HT-29 cells (LC50=9.7±0.2μM), and hepatocarcinoma HepG2 cells (LC50=22.5±1.4μM) with appreciably less hemolytic activity against human erythrocytes (LC50=213±18μM). Structure-activity relationships were investigated by synthesizing analogs of hymenochirin-1B in which Pro5, Glu6 and Asp9on the hydrophilic face of the helix were replaced by one or more L-lysine or D-lysine residues. The [D9K] analog displays the greatest increase in potency against all four cell lines (up to 6fold) but hemolytic activity also increases (LC50=174±12μM). The [D9k] and [E6k,D9k] analogs retain relatively high cytotoxic potency against the tumor cells (LC50 in the range 2.1-21μM) but show reduced hemolytic activity (LC50>300μM). The data suggest that hymenochirin-1B has therapeutic potential as a template to generate potent, non-toxic anti-cancer agents.",

keywords = "Anti-cancer, Frog skin, Host-defense peptide, Hymenochirin, Structure-activity",

author = "Samir Attoub and Hama Arafat and Milena Mechkarska and Conlon, {J. Michael}",

note = "Funding Information: This work was supported by a Faculty Support Grant and a University/National Research Foundation Grant from U.A.E. University and an award from the Terry Fox Fund for Cancer Research . The authors thank Dr. Katarina Hostanska, Department of Internal Medicine, Institute for Complementary Medicine, University Hospital of Zurich for providing the A549 cell line, Prof. Joan Massague, Howard Hughes Medical Institute, Memorial Sloan–Kettering Cancer Center for providing the MDA-MB-231 cell line, and Prof. Nico Nagelkerke, Institute of Public Health, U.A.E. University for help with data analysis.",

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doi = "10.1016/j.regpep.2013.10.006",

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AU - Attoub, Samir

AU - Arafat, Hama

AU - Mechkarska, Milena

AU - Conlon, J. Michael

N1 - Funding Information: This work was supported by a Faculty Support Grant and a University/National Research Foundation Grant from U.A.E. University and an award from the Terry Fox Fund for Cancer Research . The authors thank Dr. Katarina Hostanska, Department of Internal Medicine, Institute for Complementary Medicine, University Hospital of Zurich for providing the A549 cell line, Prof. Joan Massague, Howard Hughes Medical Institute, Memorial Sloan–Kettering Cancer Center for providing the MDA-MB-231 cell line, and Prof. Nico Nagelkerke, Institute of Public Health, U.A.E. University for help with data analysis.

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N2 - The hymenochirins are a family of cationic, amphipathic, α-helical host-defense peptides, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Of the four hymenochirins tested, hymenochirin-1B (IKLSPETKDNLKKVLKGAIKGAIVAKMV.NH2) shows the greatest cytotoxic potency against non-small cell lung adenocarcinoma A549 cells (LC50=2.5±0.2μM), breast adenocarcinoma MDA-MB-231 cells (LC50=9.0±0.3μM), colorectal adenocarcinoma HT-29 cells (LC50=9.7±0.2μM), and hepatocarcinoma HepG2 cells (LC50=22.5±1.4μM) with appreciably less hemolytic activity against human erythrocytes (LC50=213±18μM). Structure-activity relationships were investigated by synthesizing analogs of hymenochirin-1B in which Pro5, Glu6 and Asp9on the hydrophilic face of the helix were replaced by one or more L-lysine or D-lysine residues. The [D9K] analog displays the greatest increase in potency against all four cell lines (up to 6fold) but hemolytic activity also increases (LC50=174±12μM). The [D9k] and [E6k,D9k] analogs retain relatively high cytotoxic potency against the tumor cells (LC50 in the range 2.1-21μM) but show reduced hemolytic activity (LC50>300μM). The data suggest that hymenochirin-1B has therapeutic potential as a template to generate potent, non-toxic anti-cancer agents.

AB - The hymenochirins are a family of cationic, amphipathic, α-helical host-defense peptides, first isolated from skin secretions of the Congo clawed frog Hymenochirus boettgeri (Pipidae). Of the four hymenochirins tested, hymenochirin-1B (IKLSPETKDNLKKVLKGAIKGAIVAKMV.NH2) shows the greatest cytotoxic potency against non-small cell lung adenocarcinoma A549 cells (LC50=2.5±0.2μM), breast adenocarcinoma MDA-MB-231 cells (LC50=9.0±0.3μM), colorectal adenocarcinoma HT-29 cells (LC50=9.7±0.2μM), and hepatocarcinoma HepG2 cells (LC50=22.5±1.4μM) with appreciably less hemolytic activity against human erythrocytes (LC50=213±18μM). Structure-activity relationships were investigated by synthesizing analogs of hymenochirin-1B in which Pro5, Glu6 and Asp9on the hydrophilic face of the helix were replaced by one or more L-lysine or D-lysine residues. The [D9K] analog displays the greatest increase in potency against all four cell lines (up to 6fold) but hemolytic activity also increases (LC50=174±12μM). The [D9k] and [E6k,D9k] analogs retain relatively high cytotoxic potency against the tumor cells (LC50 in the range 2.1-21μM) but show reduced hemolytic activity (LC50>300μM). The data suggest that hymenochirin-1B has therapeutic potential as a template to generate potent, non-toxic anti-cancer agents.

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KW - Frog skin

KW - Host-defense peptide

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KW - Structure-activity

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ER -

Anti-tumor activities of the host-defense peptide hymenochirin-1B

Abstract

Bibliographical note

Keywords

UN SDGs

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