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Article Dans Une Revue BBA - Biochimica et Biophysica Acta Année : 2014

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

Sandrine Sagan

Résumé

: 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.

Domaines

Chimie organique
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Dates et versions

hal-00989572 , version 1 (12-05-2014)

Identifiants

Citer

Isabel D Alves, Manon Carré, Marie-Pierre Montero, Sabine Castano, Sophie Lecomte, et al.. A proapoptotic peptide conjugated to penetratin selectively inhibits tumor cell growth.. BBA - Biochimica et Biophysica Acta, 2014, 1838 (8), pp.2087-2098. ⟨10.1016/j.bbamem.2014.04.025⟩. ⟨hal-00989572⟩
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