Anti-cancer activity of targeted pro-apoptotic peptides

• Published in: Nature medicine Vol. 5; no. 9; pp. 1032 - 1038
• Main Authors: Ruoslahti, Erkki, Bredesen, Dale E, Pasqualini, Renata, Ellerby, H. Michael, Arap, Wadih, Ellerby, Lisa M, Kain, Renate, Andrusiak, Rebecca, Rio, Gabriel Del, Krajewski, Stanislaw, Lombardo, Christian R, Rao, Rammohan
• Format: Journal Article
• Language: English
• Published: United States 01-09-1999
• Subjects: Amino Acid Sequence; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Breast Neoplasms - ultrastructure; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Endothelium, Vascular - ultrastructure; Female; Humans; Intracellular Membranes - drug effects; Intracellular Membranes - pathology; Intracellular Membranes - ultrastructure; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria, Liver - drug effects; Mitochondria, Liver - pathology; Mitochondria, Liver - ultrastructure; Neoplasm Transplantation; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Peptides - therapeutic use; Protein Sorting Signals - genetics; Protein Sorting Signals - physiology; Rats; Transplantation, Heterologous; Tumor Cells, Cultured
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/12469

We have designed short peptides composed of two functional domains, one a tumor blood vessel 'homing' motif and the other a programmed cell death-inducing sequence, and synthesized them by simple peptide chemistry. The 'homing' domain was designed to guide the peptide to targeted cells and allow its internalization. The pro-apoptotic domain was designed to be nontoxic outside cells, but toxic when internalized into targeted cells by the disruption of mitochondrial membranes. Although our prototypes contain only 21 and 26 residues, they were selectively toxic to angiogenic endothelial cells and showed anti-cancer activity in mice. This approach may yield new therapeutic agents.