The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate

O'Connor, Stephen (University College Dublin, Belfield, Dublin, Ireland) ; Szwej, Emilia (University College Dublin, Belfield, Dublin, Ireland) ; Nikodinovic-Runic, Jasmina (University College Dublin, Belfield, Dublin, Ireland) ; O'Connor, Aisling (University College Dublin, Belfield, Dublin, Ireland) ; Byrne, Annette T. (Royal Xollege of Surgeons in Ireland, Dublin, Ireland) ; Devocelle, Marc (Royal College of Surgeons in Ireland, Dublin, Ireland) ; O'Donovan, Norma (Molecular Therapeutics for Cancer Ireland (MTCI), National Institute for Cellular Biotechnology (NICB), Dublin City University, Dublin, Ireland) ; Gallagher, William M. (University College Dublin, Dublin, Ireland) ; Babu, Ramesh (Centre for Research on Adaptive Nanostructures and Nano Devices, Ireland ; School of Physics, Trinity College Dublin, Dublin, Ireland) ; Kenny, Shane T. (University College Dublin, Dublin, Ireland) ; Zinn, Manfred (Empa Swiss Federal Laboratories for Materials Science and Technology, St. Gallen, Switzerland) ; Zulian, Qun Ren (Empa Swiss Federal Laboratories for Materials Science and Technology, St. Gallen, Switzerland) ; O'Connor, Kevin E. (University College Dublin, Dublin, Ireland)

The biodegradable polymer medium chain length polyhydroxyalkanoate (mclPHA), produced by Pseudomonas putida CA-3, was depolymerised and the predominant monomer (R)-3-hydroxydecanoic acid (R10) purified. R10 was conjugated to a d-peptide DP18 and its derivatives. All peptides conjugated with R10 exhibited greater anti-cancer activity compared to the unconjugated peptides. Unconjugated and conjugated peptides were cytocidal for cancer cells. Conjugation of R10 to peptides was essential for enhanced anti-proliferation activity, as unconjugated mixes did not result in enhancement of anti-cancer activity. The conjugation of R10 resulted in more rapid uptake of peptides into HeLa and MiaPaCa cells compared to unconjugated peptide. Both unconjugated and R10 conjugated peptides localized to the mitochondria of HeLa and MiaPaCa cells and induced apoptosis. Peptide conjugated with a terminally hydroxylated decanoic acid (ω-hydroxydecanoic acid) exhibited 3.3 and 6.3 fold higher IC50 values compared to R10 conjugated peptide indicating a role for the position of the hydroxyl moiety in enhancement of anti-cancer activity. Conjugation of decanoic acid (C10) to peptides resulted in similar or higher IC50 values compared to R10 conjugates but C10 conjugates did not exhibit any cancer selectivity. Combination studies showed that R10DP18L exhibited synergy with cisplatin, gemcitabine, and taxotere with IC50 values in the nanomolar range.


Note: ZINN, Manfred est un chercheur à la HES-SO, HEI-VS, depuis 2011.


Mots-clés:
Type d'article:
scientifique
Faculté:
Ingénierie et Architecture
Ecole:
HEI-VS
Institut:
Institut Technologies du vivant
Date:
2013-04
Pagination:
9 p.
Veröffentlicht in:
Biomaterials
Numérotation (vol. no.):
2013, vol. 34, no. 11, pp. 2710-2718
DOI:
ISSN:
01429612
Le document apparaît dans:

Note: The status of this file is: restricted


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