Cell-permeable peptides induce dose- and length-dependent cytotoxic effects.

Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Research Abstract Details 

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Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Abstract Text:

Alessandra K Cardozo, Buchillier,Marc Mathieu,Jianhua Chen,Fernanda Ortis,Laurence ,Nathalie Allaman-Pillet,Olivier Poirot,Stephan Kellenberger,Jacques S Beckmann,Decio L Eizirik,Christophe Bonny,Fabienne Maurer,

We have explored the threshold of tolerance of three unrelated cell types to treatments with potential cytoprotective peptides bound to Tat(48-57) and Antp(43-58) cell-permeable peptide carriers. Both Tat(48-57) and Antp(43-58) are well known for their good efficacy at crossing membranes of different cell types, their overall low toxicity, and their absence of leakage once internalised. Here, we show that concentrations of up to 100 microM of Tat(48-57) were essentially harmless in all cells tested, whereas Antp(43-58) was significantly more toxic. Moreover, all peptides bound to Tat(48-57) and Antp(43-58) triggered significant and length-dependent cytotoxicity when used at concentrations above 10 microM in all but one cell types (208F rat fibroblasts), irrespective of the sequence of the cargo. Absence of cytotoxicity in 208F fibroblasts correlated with poor intracellular peptide uptake, as monitored by confocal laser scanning fluorescence microscopy. Our data further suggest that the onset of cytotoxicity correlates with the activation of two intracellular stress signalling pathways, namely those involving JNK, and to a lesser extent p38 mitogen-activated protein kinases. These responses are of particular concern for cells that are especially sensitive to the activation of stress kinases. Collectively, these results indicate that in order to avoid unwanted and unspecific cytotoxicity, effector molecules bound to Tat(48-57) should be designed with the shortest possible sequence and the highest possible affinity for their binding partners or targets, so that concentrations below 10 microM can be successfully applied to cells without harm. Considering that cytotoxicity associated to Tat(48-57)- and Antp(43-58) bound peptide conjugates was not restricted to a particular type of cells, our data provide a general framework for the design of cell-penetrating peptides that may apply to broader uses of intracellular peptide and drug delivery.

Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Publishing Authors By Initials

AK Cardozo,V Buchillier,M Mathieu,J Chen,F Ortis,L ,N Allaman-Pillet,O Poirot,S Kellenberger,JS Beckmann,DL Eizirik,C Bonny,F Maurer,

For similar animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats research abstracts see: animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats research

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Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biochimica et biophysica acta

VOLUME: 1768

Page Numbers: 2222-34

Journal Abbreviation: Biochim. Biophys. Acta

ISSN: 0006-3002

DAY: 14

MONTH: 06

YEAR: 2007

Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 217513

Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Keywords Mesh Terms:

KEYWORDS: Rats

MESH TERMS: pharmacokinetics

Chemical & Substance for Abstract: Cell-permeable peptides induce dose- and length-dependent cytotoxic effects. Information

Substance Name: Peptides

Registry Number: 0

Grant and Affiliation Information for Cell-permeable peptides induce dose- and length-dependent cytotoxic effects.

AFFILIATION: The Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium.

Country: Netherlands

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MEDLINETA: Biochim Biophys Acta

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