HER2-targeted hybrid peptide that blocks HER2 tyrosine kinase disintegrates cancer cell membrane and inhibits tumor growth in vivo.
HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20% to 30% of breast cancers. We have recently designed a novel class of drug, the hybrid peptide, which is chemically synthesized and is composed of a target-binding peptide and a lytic peptide containing cationic-rich amino acid components that disintegrate the cell membrane, leading to cancer cell death via membrane lysis. In this study, we designed a HER2-binding peptide linked to this novel lytic peptide, which we termed the HER2-lytic hybrid peptide and assessed the cytotoxic activity of this hybrid peptide in vitro and in vivo. The HER2-lytic hybrid peptide showed high cytotoxic activity against all ovarian and breast cancer cell lines, even trastuzumab- and/or lapatinib-resistant cells, but not against normal cells. Competition assays using anti-HER2 antibody and knockdown of this receptor by siRNA confirmed the specificity of the HER2-lytic hybrid peptide. In addition, it was shown that the HER2-lytic hybrid peptide can disintegrate the cancer cell membrane of HER2-overexpressing SK-BR-3 cancer cells in only 5 minutes, but not normal cells, and block HER2 signaling. Intravenous administration of the HER2-lytic peptide in the athymic mouse implanted with BT-474 and MDA-MB-453 cells significantly inhibited tumor progression. The HER2-lytic hybrid peptide was effective even in breast cancer cell lines that are resistant to trastuzumab and/or lapatinib in vitro and in vivo. Therefore, this hybrid peptide may provide a potent treatment option for patients with cancer.
Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Megumi
M
Kawamoto
Tomohisa
T
Horibe
Masayuki
M
Kohno
Koji
K
Kawakami
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases