A Bifunctional Targeted Peptide that Blocks HER-2 Tyrosine Kinase and Disables Mitochondrial Function in HER-2-Positive Carcinoma Cells

Abstract

The HER-2 oncoprotein is commonly overexpressed in a variety of human malignancies and has become an attractive antitumor target. A number of strategies to inhibit the HER-2 receptor tyrosine kinase are currently the focus of intensive preclinical and clinical research. In the present study, we have engineered a bifunctional peptide, BHAP, which consists of two modular domains: a HER-2-targeting/neutralizing domain and a mitochondriotoxic, proapoptotic domain. The chimeric peptide is biologically active and capable of selectively triggering apoptosis of HER-2-overexpressing cancer cells in culture, even those previously described as Herceptin resistant. Furthermore, BHAP slows down growth of HER-2-overexpressing human mammary xenografts established in SCID mice. This approach can be extended to the development of tailored targeted chimeric peptides against a number of overexpressed cellular receptors implicated in the development and progression of cancer. (Cancer Res 2005; 65(15): 6891-900)

Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma

“…We made use of this unique ability of CGKRK to reach the mitochondria by using the amphiphilic proapoptotic peptide D [KLAKLAK] 2 as the payload. D [KLAKLAK] 2 has been shown to act on mitochondria, the target of CGKRK (10), and several reports have described the antitumor activities of D [KLAKLAK] 2 (and some other peptides with similar activities), when selectively delivered to a target tissue (11)(12)(13)(14)(15)(27)(28)(29). The main limitation of these treatments has been that the D [KLA-KLAK] 2 peptide is highly toxic at the doses required for tumor treatment even with specific targeting.…”

“…However, when internalized into eukaryotic cells, D [KLAKLAK] 2 disrupts the mitochondrial membrane, which is similar to bacteria membranes, and initiates apoptotic cell death (10). Conjugating D [KLAKLAK] 2 with homing peptides has produced compounds that specifically accumulate at the homing target, causing cell death (11)(12)(13)(14)(15) 2 , however, is a highly toxic compound, even when specifically targeted to tumors (11,13). Administering toxic drugs in a nanoparticle formulation can reduce toxicity.…”

ErbB receptors: from oncogenes to targeted cancer therapies

“…As with the parental mAb, AHNP is capable of disabling p185 her2/neu receptor function in vitro and in vivo, although it has lower affinity for p185 her2/neu . The activity of AHNP has been verified in several other labs (66,67). Unlike the parental mAb, AHNP was unable to downregulate p185 her2/neu expression at the cell surface, indicating that the small molecule functioned differently to inhibit p185 her2/neu .…”

Mitochondria as therapeutic targets for cancer chemotherapy

“…Treatment of mice with this peptide postponed the development of cancer in model of spontaneously developing prostate adenocarcinoma (Arap et al, 2002). Similarly, (KLAK-LAK) 2 has been fused to a peptide that inhibits the ErbB-2 receptor kinase (Fantin et al, 2005). The resulting fusion protein specifically affects mitochondria of cells that express ErbB-2, but not those of cells lacking ErbB-2 expression, causing MOMP and DC m dissipation.…”

“…The resulting fusion protein specifically affects mitochondria of cells that express ErbB-2, but not those of cells lacking ErbB-2 expression, causing MOMP and DC m dissipation. In addition, this peptide has been used to induce massive apoptosis in vivo, in mice carrying established human breast cancer xenografts (Fantin et al, 2005). These experiments provide a proof-ofconcept for the strategy of targeting toxic hybrid molecules to cancer cells, first to surface receptors and then to mitochondria.…”