Journal
EXPERIMENTAL AND MOLECULAR PATHOLOGY
Volume 99, Issue 3, Pages 426-434Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yexmp.2015.08.021
Keywords
Antimicrobial peptide; Breast cancer; D-amino acid; Cytotoxicity; Pleurocidin
Categories
Funding
- Canadian Breast Cancer Foundation-Atlantic Region [R15D07]
- Canadian Institutes for Health Research (CIHR) [MOP-74493]
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- CIHR
- Canada Foundation for Innovation
- Atlantic Innovation Fund
- NSERC
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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. (C) 2015 Elsevier Inc All rights reserved.
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