A single replacement of histidine to arginine in EGFR-lytic hybrid peptide demonstrates the improved anticancer activity.

Abstract

We previously reported that novel targeted "hybrid peptide" in which epidermal growth factor receptor (EGFR) binding peptide was conjugated with lytic-type peptide had selective cytotoxic activity to EGFR expressing cancer cell lines, and in vivo analysis revealed that this EGFR-lytic peptide displayed significant antitumor activity in a xenograft model of human breast cancer which was resistant to tyrosine kinase inhibitor drugs. As an attempt to improve the selective anticancer activity of EGFR-lytic peptide, we modified the EGFR-binding peptide through introducing the mutation of amino acid according to biophysical analysis by biomolecular interaction and circular dichroism (CD) spectra. When cytotoxic activity of EGFR-lytic or EGFR(2R)-lytic hybrid peptides was investigated in various human cancer and normal cell lines, it was demonstrated that EGFR(2R)-lytic, in which second histidine (H) of EGFR-binding peptide was replaced to arginine (R) had 1.2-1.9-fold higher cytotoxic activity than that of original EGFR-lytic peptide. In vivo analysis also revealed that this modified peptide displayed significant antitumor activity at as low as 1 mg/kg dosage. These results suggest that mutated arginine on EGFR-lytic peptide produces higher binding ability to EGFR on cancer cells, and thereby the improved anticancer activity.

• Authors: Noriko Tada, Tomohisa Horibe, Mari Haramoto, Koji Ohara, Masayuki Kohno, Koji Kawakami
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 407 Issue 2 Pg. 383-8 (Apr 08 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21396910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Peptides
• Recombinant Fusion Proteins
• Histidine
• Arginine
• ErbB Receptors

Topics

• Amino Acid Substitution
• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Arginine (chemistry, genetics)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• ErbB Receptors (chemistry, genetics, therapeutic use)
• Female
• Histidine (chemistry, genetics)
• Humans
• Mice
• Mice, Nude
• Mutation
• Peptides (chemistry, genetics, therapeutic use)
• Recombinant Fusion Proteins (chemistry, genetics, therapeutic use)
• Xenograft Model Antitumor Assays