Antimicrobial cyclic decapeptides with anticancer activity.
Antimicrobial peptides have been considered as potential candidates for cancer therapy. We report here the cytotoxicity of a library of 66 antibacterial cyclodecapeptides on human carcinoma cell lines, and their effects on apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase (PARP)] and cell signaling proteins (p53 and ERK1/2) in cultured human cervical carcinoma cells. A design of experiments approach permitted to analyze the results of a subset of 16 peptides and define rules for high anticancer activity against MDA-MB-231 breast carcinoma cells. Eight peptides were identified with IC(50) values ranging from 18.5 to 57.5 μM against the five cell lines tested, being HeLa cells the most sensitive. Among these sequences, BPC88, BPC96, BPC98, and BPC194 displayed specificity and high cytotoxicity against HeLa cells (IC(50) of 22.5-38.5 μM), showed low hemolytic activity and low cytotoxicity to non-malignant fibroblasts, and were stable to proteases in human serum. Induction of apoptosis by these peptides was observed and the apoptotic effect of BPC88 and BPC96 caused a marked decrease on the activated form of ERK1/2 kinase and an induction of p53. We further showed that BPC96 at low doses synergized the cytotoxic effect of cisplatin. These findings suggest that cyclic decapeptides may represent novel anticancer agents providing a new strategy in cancer therapy.
Feliu
Lidia
L
LIPPSO, Department of Chemistry, University of Girona, Campus Montilivi, E-17071 Girona, Spain.
Oliveras
Glòria
G
Cirac
Anna D
AD
Besalú
Emili
E
Rosés
Cristina
C
Colomer
Ramon
R
Bardají
Eduard
E
Planas
Marta
M
Puig
Teresa
T
D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects; D009842:Oligopeptides / Q000627:therapeutic use; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; C555919:BPC96 peptide; D009842:Oligopeptides; D019151:Peptide Library; D010456:Peptides, Cyclic; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002945:Cisplatin