Enhanced killing of breast cancer cells by a d-amino acid analog of the winter flounder-derived pleurocidin NRC-03

Ashley L. Hilchie; Evan F. Haney; Devanand M. Pinto; Robert E.W. Hancock; David W. Hoskin

doi:10.1016/j.yexmp.2015.08.021

Enhanced killing of breast cancer cells by a d-amino acid analog of the winter flounder-derived pleurocidin NRC-03

Ashley L. Hilchie, Evan F. Haney, Devanand M. Pinto, Robert E.W. Hancock, David W. Hoskin

Medicine

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

28 Citas (Scopus)

Resumen

Cationic antimicrobial peptides (CAPs) defend against pathogens and, in some cases, exhibit potent anticancer activities. We previously reported that the pleurocidin NRC-03 causes lysis of breast cancer and multiple myeloma cells. NRC-03 also reduces the EC₅₀ of other cytotoxic compounds and prevents tumor growth in vivo. However, the therapeutic utility of NRC-03 may be limited by its susceptibility to degradation by proteases. The goal of this study was to characterize the anticancer activities of a d-amino acid analog of NRC-03 ([D]-NRC-03) that was predicted to be resistant to proteolytic degradation. Unlike NRC-03, [D]-NRC-03 was not degraded by human serum or trypsin and, in comparison to NRC-03, showed increased killing of breast cancer cells, including multidrug-resistant cells; however, [D]-NRC-03 was somewhat more cytotoxic than NRC-03 for several types of normal cells. Importantly, [D]-NRC-03 was more effective than NRC-03 in vivo since 4-fold less peptide was required for an equivalent inhibitory effect on the growth of breast cancer cell xenografts in immune-deficient mice. These findings demonstrate that a d-amino acid analog of NRC-03 overcomes a major limitation to the therapeutic use of NRC-03, namely peptide stability. Further modification of [D]-NRC-03 is required to improve its selectivity for cancer cells.

Idioma original	English
Páginas (desde-hasta)	426-434
Número de páginas	9
Publicación	Experimental and Molecular Pathology
Volumen	99
N.º	3
DOI	https://doi.org/10.1016/j.yexmp.2015.08.021
Estado	Published - dic. 1 2015

Nota bibliográfica

Funding Information:
This study was funded by a grant to DH from the Canadian Breast Cancer Foundation-Atlantic Region (funding reference number R15D07 ) and to RH from the Canadian Institutes for Health Research (CIHR) (funding reference number MOP-74493 ). AH was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC) and a postdoctoral fellowship from CIHR . EH was supported by a postdoctoral fellowship from CIHR. We acknowledge the support of the Canada Foundation for Innovation , the Atlantic Innovation Fund , NSERC , and other partners that fund the Facilities for Materials Characterization, managed by the Institute for Research in Materials, for use of the scanning electron microscope. DH holds the Canadian Breast Cancer Foundation-Atlantic Region Endowed Chair in Breast Cancer Research and RH holds a Canada Research Chair. We also acknowledge Dr. Carolyn Doucette and Ken Chisholm for their technical assistance.

Publisher Copyright:
© 2015 Elsevier Inc.

ASJC Scopus Subject Areas

Pathology and Forensic Medicine
Molecular Biology
Clinical Biochemistry

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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title = "Enhanced killing of breast cancer cells by a d-amino acid analog of the winter flounder-derived pleurocidin NRC-03",

abstract = "Cationic antimicrobial peptides (CAPs) defend against pathogens and, in some cases, exhibit potent anticancer activities. We previously reported that the pleurocidin NRC-03 causes lysis of breast cancer and multiple myeloma cells. NRC-03 also reduces the EC50 of other cytotoxic compounds and prevents tumor growth in vivo. However, the therapeutic utility of NRC-03 may be limited by its susceptibility to degradation by proteases. The goal of this study was to characterize the anticancer activities of a d-amino acid analog of NRC-03 ([D]-NRC-03) that was predicted to be resistant to proteolytic degradation. Unlike NRC-03, [D]-NRC-03 was not degraded by human serum or trypsin and, in comparison to NRC-03, showed increased killing of breast cancer cells, including multidrug-resistant cells; however, [D]-NRC-03 was somewhat more cytotoxic than NRC-03 for several types of normal cells. Importantly, [D]-NRC-03 was more effective than NRC-03 in vivo since 4-fold less peptide was required for an equivalent inhibitory effect on the growth of breast cancer cell xenografts in immune-deficient mice. These findings demonstrate that a d-amino acid analog of NRC-03 overcomes a major limitation to the therapeutic use of NRC-03, namely peptide stability. Further modification of [D]-NRC-03 is required to improve its selectivity for cancer cells.",

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AU - Hancock, Robert E.W.

AU - Hoskin, David W.

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Enhanced killing of breast cancer cells by a d-amino acid analog of the winter flounder-derived pleurocidin NRC-03

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODS de las Naciones Unidas

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