Enhanced killing of breast cancer cells by a d-amino acid analog of the winter flounder-derived pleurocidin NRC-03.
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.
Department of Microbiology and Immunology, Dalhousie University, Halifax B3H 4R2, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver V6T 1Z4, Canada.
Ashley L
AL
Hilchie
Department of Microbiology and Immunology, University of British Columbia, Vancouver V6T 1Z4, Canada.
Evan F
EF
Haney
Department of Chemistry, Dalhousie University, Halifax B3H 4R2, Canada; National Research Council Institute for Marine Biosciences, Halifax B3H 3Z1, Canada.
Devanand M
DM
Pinto
Department of Microbiology and Immunology, University of British Columbia, Vancouver V6T 1Z4, Canada.
Robert E W
RE
Hancock
Department of Microbiology and Immunology, Dalhousie University, Halifax B3H 4R2, Canada; Department of Pathology, Dalhousie University, Halifax B3H 4R2, Canada; Department of Surgery, Dalhousie University, Halifax B3H 4R2, Canada. Electronic address: d.w.hoskin@dal.ca.
David W
DW
Hoskin
D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D016923:Cell Death; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D029941:Fish Proteins / Q000737:chemistry / Q000494:pharmacology*; D005432:Flounder; D006801:Humans; D016513:Mice, SCID
D000596:Amino Acids; D029941:Fish Proteins; C105851:pleurocidin
Antimicrobial peptide; Breast cancer; Cytotoxicity; Pleurocidin; d-amino acid