HER2-Targeted Hybrid Peptide That Blocks HER2 Tyrosine Kinase Disintegrates Cancer Cell Membrane and Inhibits Tumor GrowthIn Vivo

Abstract

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. Mol Cancer Ther; 12(4); 384-93. Ó2013 AACR.

An investigation on the anti-tumor properties of FSH33-53-Lytic

“…Cytotoxic activity of EGFR-lytic or HER2-Lytic peptide was investigated in various normal cell lines. It was found that normal cells were only minimally susceptible to the novel hybrid peptides [12,13]. These encouraging preclinical data suggest that the tumor receptor-targeting hybrid peptides would be a new possible mechanism in cancer targeting therapy.…”

“…To improve tumor targeting effect, several peptide ligands of receptors expressed in tumor cells are conjugated with the Lytic peptide. Frequently-seen receptors are transferrin receptor (TfR) [11], human epidermal growth receptor 2 [12], epidermal growth factor receptor (EGFR) [13] and neuropilin-1 (NRP1) [14], etc. These hybird peptides have cytotoxicity and selectivity to cancer cells in both vitro and vivo.…”

Targeted Nanodiamonds as Phenotype-Specific Photoacoustic Contrast Agents for Breast Cancer

“…As a result, cellular uptake was enhanced leading to rapid entrance of nanoparticles into the tumor cells. In addition, the peptide-targeting moiety may have less immunogenicity and cytotoxicity than antibody-based ones because of its lower molecular weight [54]. Uptake of the peptide-nanoparticle conjugate in 4T1.2-neu breast cancer cells was appreciably higher than that of PEGylated INDs (Figure 5a).…”

Synergetic cytotoxic activity toward breast cancer cells enhanced by the combination of Antp-TPR hybrid peptide targeting Hsp90 and Hsp70-targeted peptide

“…Thus, it is suggested that the inhibition of Hsp70 might exert effectively for cytotoxic activity via the inhibition of Hsp90 even in Hsp70-low expressing cancer cells. It has been reported that BT474 and MDA-MB-361 are Her2 high-expressing, and BT20 and MDA-MB-231 are Her2 low-expressing cancer cells, and that BT20, MDA-MB-361, and BT474 have mutations in PIK3CA , and only MDA-MB-231 has KRAS mutation among these cell lines [27, 28]. It has been also reported that BT474 is sensitive to both trastuzumab and lapatinib, and that MDA-MB-361 is sensitive to trastuzumab but resistant to lapatinib [29].…”