Molecular mechanisms of anticancer action and cell selectivity of short α-helical peptides

Cuixia Chen, Jing Hu, Ping Zeng, Fang Pan, Mohammed Yaseen, Hai Xu, Jian R. Lu

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1552-1561
Number of pages10
JournalBiomaterials
Volume35
Issue number5
DOIs
Publication statusPublished - 1 Feb 2014
Externally publishedYes

Fingerprint

Peptides
Cells
Neoplasms
Death Domain Receptors
Functional materials
Fluidity
Biocompatible Materials
Cell death
Cell membranes
Biocompatibility
Heterografts
Biomaterials
Pharmaceutical Preparations
Tumors
Cell Death
Cell Membrane
Proteins
Membranes
Delivery of Health Care
Growth

Keywords

  • Antimicrobial peptide
  • Anticancer activity
  • Cell selectivity
  • Membrane permeabilization
  • Cell apoptosis
  • Xenograft model

Cite this

Chen, Cuixia ; Hu, Jing ; Zeng, Ping ; Pan, Fang ; Yaseen, Mohammed ; Xu, Hai ; Lu, Jian R. / Molecular mechanisms of anticancer action and cell selectivity of short α-helical peptides. In: Biomaterials. 2014 ; Vol. 35, No. 5. pp. 1552-1561.
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Molecular mechanisms of anticancer action and cell selectivity of short α-helical peptides. / Chen, Cuixia; Hu, Jing; Zeng, Ping; Pan, Fang; Yaseen, Mohammed; Xu, Hai; Lu, Jian R.

In: Biomaterials, Vol. 35, No. 5, 01.02.2014, p. 1552-1561.

Research output: Contribution to journalArticle

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T1 - Molecular mechanisms of anticancer action and cell selectivity of short α-helical peptides

AU - Chen, Cuixia

AU - Hu, Jing

AU - Zeng, Ping

AU - Pan, Fang

AU - Yaseen, Mohammed

AU - Xu, Hai

AU - Lu, Jian R.

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N2 - 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.

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