A novel hybrid peptide targeting EGFR-expressing cancers.
Several potential molecular-targeted anticancer drugs focus on the inhibition of receptor tyrosine kinase and tumour growth, but these tyrosine kinase inhibitors (TKI) have been reported that the mutations of kinase-related signal molecule genes in cancer cells lead to the drug resistance. To overcome this issue, we have designed a novel targeting anticancer 'hybrid-peptide' EGFR-lytic peptide, in which epidermal growth factor receptor (EGFR) binding peptide is conjugated with a newly designed lytic-type peptide containing cationic-rich amino acids that disintegrates the cell membrane to kill cancer cells. In this report, cytotoxic activity of EGFR-lytic peptide was investigated in various human cancer and normal cell lines. It was found that the resulting conformational change in the novel lytic peptide enabled it to bind selectively to the membrane of cancer cells, and due to its acquired synergistic action, hybrid peptide demonstrated selective destruction of cancer cells as swiftly as 10 min after exposure. Treatment with EGFR-lytic peptide exerted a sufficient in vitro cytotoxic activity against TKI-resistant cancer cells with K-ras mutations. Moreover, in vivo analyses revealed that this peptide displayed significant antitumour activity in mouse xenograft models of both human K-ras mutation negative and positive cancers. Thus, hybrid peptide can be a unique and powerful tool for a new cancer-targeted therapy.
Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.
Masayuki
M
Kohno
Tomohisa
T
Horibe
Mari
M
Haramoto
Yoshiaki
Y
Yano
Koji
K
Ohara
Oumi
O
Nakajima
Katsumi
K
Matsuzaki
Koji
K
Kawakami
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism* / Q000627:therapeutic use; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D050506:Mutant Chimeric Proteins / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D050506:Mutant Chimeric Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline