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Anti-cancer activity of targeted pro-apoptotic peptides

Abstract

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.

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Figure 1: Computer-generated model and amino-acid sequence of CNGRC-GGD(KLAKLAK)2.
Figure 2: D(KLAKLAK)2 disrupts mitochondrial membranes.
Figure 3: CNGRC-GG-D(KLAKLAK)2 and (RGD-4C)-GG-D(KLAKLAK)2 induce apoptosis.
Figure 4: CNGRC-GG-D(KLAKLAK)2 induces apoptosis and mitochondrial swelling in DMECs.
Figure 5: Electron microscopic studies of cultured cells.
Figure 6: Treatment of nude mice bearing MDA-MB-435-derived human breast carcinoma xenografts with CNGRC-GG-D(KLAKLAK)2.
Figure 7: Treatment of nude mice bearing MDA-MB-435-derived human breast carcinoma xenografts with (RGD-4C)-GG-D(KLAKLAK)2.

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Acknowledgements

We thank W.K. Cavenee and G. Salvesen for comments and critical reading of the manuscript. This work was supported by grants CA74238, CA28896 (to ER) NS33376 and Cancer Center support grant CA30199 (to R.P., D.B. and E.R.) from the National Cancer Institute (USA), and DAMD17-98-1-8581 (to D.B. and R.P.) from the DOD-PCRP. H.M.E. is the recipient of a NS10050 NRSA senior fellowship grant. W.A. is the recipient of a CaP CURE award.

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Correspondence to Erkki Ruoslahti, Dale E. Bredesen or Renata Pasqualini.

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Ellerby, H., Arap, W., Ellerby, L. et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 5, 1032–1038 (1999). https://doi.org/10.1038/12469

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