Molecular mechanisms of anticancer action and cell selectivity of short α-helical peptides.
Development of functional biomaterials and drugs with good biocompatibility towards host cells but with high potency against cancer cells is a challenging endeavor. By drawing upon the advantageous features of natural antimicrobial peptides and α-helical proteins, we have designed a new class of short α-helical peptides G(IIKK)(n)I-NH2 (n = 1-4) with different potency and high selectivity against cancer cells. We show that the peptides with n = 3 and 4 kill cancer cells effectively whilst remaining benign to the host cells at their working concentrations, through mechanistic processes similar to their bactericidal effects. The high cell selectivity could stem from their preferential binding to the outer cell membranes containing negative charges and high fluidity. In addition to rapid membrane-permeabilizing capacities, the peptides can also induce the programmed cell death of cancer cells via both mitochondrial pathway and death receptor pathway, without inducing non-specific immunogenic responses. Importantly, these peptides can also inhibit tumor growth in a mouse xenograft model without eliciting side effects. Whilst this study reveals the clinical potential of these peptides as potent drugs and for other medical and healthcare applications, it also points to the significance of fundamental material research in the future development of highly selective peptide functional materials.
Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
Cuixia
C
Chen
Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
Jing
J
Hu
Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
Ping
P
Zeng
Biological Physics Laboratory, School of Physics and Astronomy, University of Manchester, Schuster Building, Manchester M13 9PL, UK.
Fang
F
Pan
Biological Physics Laboratory, School of Physics and Astronomy, University of Manchester, Schuster Building, Manchester M13 9PL, UK.
Mohammed
M
Yaseen
Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China. Electronic address: xuh@upc.edu.cn.
Hai
H
Xu
Biological Physics Laboratory, School of Physics and Astronomy, University of Manchester, Schuster Building, Manchester M13 9PL, UK. Electronic address: j.lu@manchester.ac.uk.
Jian R
JR
Lu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D004354:Drug Screening Assays, Antitumor; D005456:Fluorescent Dyes; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D017931:DNA Primers; D005456:Fluorescent Dyes; D010455:Peptides
Anticancer activity; Antimicrobial peptide; Cell apoptosis; Cell selectivity; Membrane permeabilization; Xenograft model