title: Penetratin-mediated delivery enhances the antitumor activity of the cationic antimicrobial peptide Magainin II.
abstract: Cationic antimicrobial peptides (CAPs) with antitumor activity have potential for use as novel antitumor agents because of their lower risk for induction of resistance. Of these peptides, magainin II (MG2) exhibited cytotoxicity in tumor cells only at high concentrations, likely due to the inefficiency of MG2 in cell membrane binding and cell entry. Conjugation to a cell-penetrating peptide (CPP) might enhance the cytotoxicity of MG2 in tumor cells. Here, we constructed a fusion peptide MG2A by conjugating MG2 to the N-terminus of the CPP penetratin (Antp). It was found that the fusion peptide MG2A is more potent than unconjugated MG2 at tumor cell killing. The IC50s of MG2A for the tumor cells tested were at least 30 times lower than the IC50s of unconjugated MG2. These data indicate that conjugation to Antp significantly enhanced the cytotoxicity of MG2 in tumor cells. Moreover, the IC50s of MG2A for tumor cells are within 2 to 3 μM, which are about three to five times lower than the IC50 for normal cells. Furthermore, chondroitin sulfate (CS) was found to be overexpressed on the surface of the tested tumor cells, and the cytotoxicity of MG2A could be inhibited by the addition of exogenous CS. These results suggest that binding of Antp to CS on tumor cells might be one important cause for the selective cytotoxicity of MG2A in tumor cells. Taken together, conjugation of MG2 to Antp can significantly enhance its antitumor activity, and the fusion of CAP to Antp might be an alternative for cancer-targeted therapy.
authors.affiliation: Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University , Chengdu 610041, China .
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Wan
authors.forename: Jingqiu
authors.initials: J
authors.lastname: Cheng
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides; D016543:Central Nervous System Neoplasms / Q000188:drug therapy; D002522:Chlorocebus aethiops; D002809:Chondroitin Sulfates / Q000378:metabolism; D004337:Drug Carriers / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007687:Kidney Tubules, Proximal / Q000166:cytology; D008175:Lung Neoplasms / Q000188:drug therapy; D054806:Magainins / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D051381:Rats; D012878:Skin Neoplasms / Q000188:drug therapy; D014709:Vero Cells; D029867:Xenopus Proteins / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D054806:Magainins; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus; D002809:Chondroitin Sulfates; C414409:penetratin; D020169:Caspases
keywords: cancer-targeted therapy; cationic antimicrobial peptide; cell-penetrating peptide