Pleurocidin-family cationic antimicrobial peptides are cytolytic for breast carcinoma cells and prevent growth of tumor xenografts

Ashley L. Hilchie, Carolyn D. Doucette, Devanand M. Pinto, Aleksander Patrzykat, Susan Douglas, David W. Hoskin

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Resumen

Introduction: Cationic antimicrobial peptides (CAPs) defend against microbial pathogens; however, certain CAPs also exhibit anticancer activity. The purpose of this investigation was to determine the effect of the pleurocidin-family CAPs, NRC-03 and NRC-07, on breast cancer cells.Methods: MTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) and acid phosphatase cell-viability assays were used to assess NRC-03- and NRC-07-mediated killing of breast carcinoma cells. Erythrocyte lysis was determined with hemolysis assay. NRC-03 and NRC-07 binding to breast cancer cells and normal fibroblasts was assessed with fluorescence microscopy by using biotinylated-NRC-03 and -NRC-07. Lactate dehydrogenase-release assays and scanning electron microscopy were used to evaluate the effect of NRC-03 and NRC-07 on the cell membrane. Flow-cytometric analysis of 3,3'-dihexyloxacarbocyanine iodide- and dihydroethidium-stained breast cancer cells was used to evaluate the effects of NRC-03 and NRC-07 on mitochondrial membrane integrity and reactive oxygen species (ROS) production, respectively. Tumoricidal activity of NRC-03 and NRC-07 was evaluated in NOD SCID mice bearing breast cancer xenografts.Results: NRC-03 and NRC-07 killed breast cancer cells, including drug-resistant variants, and human mammary epithelial cells but showed little or no lysis of human dermal fibroblasts, umbilical vein endothelial cells, or erythrocytes. Sublethal doses of NRC-03 and, to a lesser extent, NRC-07 significantly reduced the median effective concentration (EC 50) of cisplatin for breast cancer cells. NRC-03 and NRC-07 bound to breast cancer cells but not fibroblasts, suggesting that killing required peptide binding to target cells. NRC-03- and NRC-07-mediated killing of breast cancer cells correlated with expression of several different anionic cell-surface molecules, suggesting that NRC-03 and NRC-07 bind to a variety of negatively-charged cell-surface molecules. NRC-03 and NRC-07 also caused significant and irreversible cell-membrane damage in breast cancer cells but not in fibroblasts. NRC-03- and NRC-07-mediated cell death involved, but did not require, mitochondrial membrane damage and ROS production. Importantly, intratumoral administration of NRC-03 and NRC-07 killed breast cancer cells grown as xenografts in NOD SCID mice.Conclusions: These findings warrant the development of stable and targeted forms of NRC-03 and/or NRC-07 that might be used alone or in combination with conventional chemotherapeutic drugs for the treatment of breast cancer.

Idioma originalEnglish
Número de artículoR102
PublicaciónBreast Cancer Research
Volumen13
N.º5
DOI
EstadoPublished - oct. 24 2011

Nota bibliográfica

Funding Information:
This work was funded by a grant to D Hoskin from the Canadian Breast Cancer Foundation-Atlantic Region. A Hilchie was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC) and a Trainee Award from the Cancer Research Training Program, with funding from the Canadian Cancer Society. C Doucette was supported by an NSERC Postgraduate Scholarship and a Nova Scotia Health Research Foundation Student Research Award. We also 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.

ASJC Scopus Subject Areas

  • Oncology
  • Cancer Research

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