dc.contributor.author | Hilchie, Ashley | |
dc.date.accessioned | 2012-11-20T15:48:32Z | |
dc.date.available | 2012-11-20T15:48:32Z | |
dc.date.issued | 2012-11-20 | |
dc.identifier.uri | http://hdl.handle.net/10222/15713 | |
dc.description.abstract | Cationic antimicrobial peptides (CAPs) are small peptides that constitute an important defence against microbial pathogens. Certain CAPs also possess anticancer properties. NRC-03 and NRC-07 are pleurocidins derived from winter and yellowtail flounder, respectively. The purpose of this investigation was to study the anticancer properties of NRC-03 and NRC-07. NRC-03 and NRC-07 killed breast cancer cells, including P-glycoprotein-overexpressing cells, in a time-dependent manner that peaked at 4 h. NRC-03 and NRC-07 lysed breast cancer cells by a mechanism that involved cell binding, mitochondrial destabilization, nuclear localization, and significant membrane damage. Interestingly, NRC-07, but not NRC-03, caused DNA fragmentation. NRC-03 and NRC-07 killed normal human epithelial cells, but did not kill endothelial cells or fibroblasts, or lyse human erythrocytes. NRC-03, and to a lesser extent NRC-07, had chemo-sensitizing properties, suggesting promise for their inclusion in combinational treatment regimens. Importantly, intratumoural injections of NRC-03 or NRC-07 inhibited tumour growth in a mouse model of breast cancer. Fetal bovine serum dose-dependently reduced cell killing by NRC-03. NRC-03 was degraded in human and mouse serum, which limited its potency. NRC-03- and NRC-07-induced cytotoxicity correlated with expression of several different negatively-charged molecules, rationalizing the generation of [D]-NRC-03, which carries the same positive charge as NRC-03, and was more potent but less selective for cancer cells than NRC-03. [D]-NRC-03 was also cytolytic and exhibited in vivo anticancer properties. To further test the clinical potential of NRC-03- and NRC-07-resistant cells were generated. NRC-03 and NRC-07 bound to resistant cells to a lesser extent than parental cells and were phenotypically distinct. Importantly, NRC-03- and NRC-07-resistant cells were killed by chemotherapeutic drugs, as well as [D]-NRC-03. These studies demonstrate that NRC-03, NRC-07, and [D]-NRC-03 are cytolytic peptides that kill breast cancer cells in vitro and in vivo. While more potent than NRC-03, [D]-NRC-03 requires further modification to minimize its toxicity toward normal cells. Although cancer cells may become resistant to NRC-03 and NRC-07 over time, resistant cells are still killed by other cytotoxic drugs, thereby reinforcing the value of adding these peptides to combinational regimens for the treatment of breast cancer. | en_US |
dc.language.iso | en | en_US |
dc.subject | cationic antimicrobial peptide | en_US |
dc.subject | breast cancer | en_US |
dc.title | Studies on the anticancer properties of pleurocidins: a preclinical evaluation | en_US |
dc.date.defence | 2011-08-05 | |
dc.contributor.department | Department of Microbiology & Immunology | en_US |
dc.contributor.degree | Doctor of Philosophy | en_US |
dc.contributor.external-examiner | Dr. Spencer Gibson | en_US |
dc.contributor.graduate-coordinator | Dr. Brent Johnston | en_US |
dc.contributor.thesis-reader | Dr. Aleksander Patrzykat | en_US |
dc.contributor.thesis-reader | Dr. Roy Duncan | en_US |
dc.contributor.thesis-reader | Dr. Susan Douglas | en_US |
dc.contributor.thesis-supervisor | Dr. David Hoskin | en_US |
dc.contributor.ethics-approval | Received | en_US |
dc.contributor.manuscripts | Not Applicable | en_US |
dc.contributor.copyright-release | Not Applicable | en_US |