The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate.
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 IC(50) 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 IC(50) 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 IC(50) values in the nanomolar range.
School of Biomolecular and Biomedical Sciences and Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Stephen
S
O'Connor
Emilia
E
Szwej
Jasmina
J
Nikodinovic-Runic
Aisling
A
O'Connor
Annette T
AT
Byrne
Marc
M
Devocelle
Norma
N
O'Donovan
William M
WM
Gallagher
Ramesh
R
Babu
Shane T
ST
Kenny
Manfred
M
Zinn
Qun Ren
QR
Zulian
Kevin E
KE
O'Connor
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology*; D001673:Biodegradation, Environmental; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D003652:Decanoic Acids / Q000737:chemistry / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000077143:Docetaxel; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D018613:Microscopy, Confocal; D054813:Polyhydroxyalkanoates / Q000737:chemistry / Q000494:pharmacology*; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology; D000093542:Gemcitabine
D016588:Anticarcinogenic Agents; D023181:Antimicrobial Cationic Peptides; D001672:Biocompatible Materials; D003652:Decanoic Acids; D054813:Polyhydroxyalkanoates; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C031071:decanoic acid; C017552:myrmicacin; D002945:Cisplatin; D000093542:Gemcitabine