A proapoptotic peptide conjugated to penetratin selectively inhibits tumor cell growth.

Abstract

The peptide KLA (acetyl-(KLAKLAK)2-NH2), which is rather non toxic for eukaryotic cell lines, becomes active when coupled to the cell penetrating peptide, penetratin (Pen), by a disulfide bridge. Remarkably, the conjugate KLA-Pen is cytotoxic, at low micromolar concentrations, against a panel of seven human tumor cell lines of various tissue origins, including cells resistant to conventional chemotherapy agents but not to normal human cell lines. Live microscopy on cells possessing fluorescent labeled mitochondria shows that in tumor cells, KLA-Pen had a strong impact on mitochondria tubular organization instantly resulting in their aggregation, while the unconjugated KLA and pen peptides had no effect. But, mitochondria in various normal cells were not affected by KLA-Pen. The interaction with membrane models of KLA-Pen, KLA and penetratin were studied using dynamic light scattering, calorimetry, plasmon resonance, circular dichroism and ATR-FTIR to unveil the mode of action of the conjugate. To understand the selectivity of the conjugate towards tumor cell lines and its action on mitochondria, lipid model systems composed of zwitterionic lipids were used as mimics of normal cell membranes and anionic lipids as mimics of tumor cell and mitochondria membrane. A very distinct mode of interaction with the two model systems was observed. KLA-Pen may exert its deleterious and selective action on cancer cells by the formation of pores with an oblique membrane orientation and establishment of important hydrophobic interactions. These results suggest that KLA-Pen could be a lead compound for the design of cancer therapeutics.

• Authors: Isabel D Alves, Manon Carré, Marie-Pierre Montero, Sabine Castano, Sophie Lecomte, Rodrigue Marquant, Pascaline Lecorché, Fabienne Burlina, Christophe Schatz, Sandrine Sagan, Gérard Chassaing, Diane Braguer, Solange Lavielle
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1838 Issue 8 Pg. 2087-98 (Aug 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24796502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Carrier Proteins
• Cell-Penetrating Peptides
• Intercellular Signaling Peptides and Proteins
• KLA peptide
• Liposomes
• Membrane Lipids
• Peptides
• penetratin

Topics

• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Calorimetry, Differential Scanning
• Carrier Proteins (pharmacology)
• Cell-Penetrating Peptides
• Circular Dichroism
• Humans
• Intercellular Signaling Peptides and Proteins
• Liposomes
• Membrane Lipids (metabolism)
• Mitochondria (drug effects)
• Mitochondrial Membranes (drug effects)
• Neoplasms (drug therapy, pathology)
• Peptides (chemistry, pharmacology)
• Spectroscopy, Fourier Transform Infrared
• Tumor Cells, Cultured