A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells

Détails

ID Serval
serval:BIB_455760477805
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells
Périodique
Oncogene
Auteur(s)
Michod  D., Yang  J. Y., Chen  J., Bonny  C., Widmann  C.
ISSN
0950-9232 (Print)
Statut éditorial
Publié
Date de publication
11/2004
Volume
23
Numéro
55
Pages
8971-8
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Nov 25
Résumé
Treatment of many cancers relies on the combined action of several genotoxins, but the detrimental effect of these drugs on normal cells can cause severe side effects. One major challenge in anticancer therapy is therefore to increase the selectivity of current treatments toward cancer cells in order to spare normal cells. We have recently demonstrated that a RasGAP caspase cleavage fragment is able to sensitize HeLa cells towards cisplatin-induced apoptosis. Here, we extend this observation by showing that this fragment also enhances cell death induced by adriamycin and mitoxantrone, two other widely used genotoxins. Furthermore, we have delineated a short sequence within this fragment that still bears the genotoxin-sensitization property. The peptide encoded by this sequence, when fused to the TAT cell permeation sequence, potently sensitized a number of tumors cells, but not normal cells, towards apoptosis induced by cisplatin, adriamycin and mitoxantrone. This sensitization effect was not mediated through modulation of NFkappaB activity or activation of the JNK and p38 MAPK pathways. Our results demonstrate the feasibility in enhancing the efficacy of currently used drugs to selectively kill cancer cells using peptides derived from pro-apoptotic caspase substrate fragments.
Mots-clé
Apoptosis Blotting, Western Cell Line, Tumor Cisplatin/pharmacology Dose-Response Relationship, Drug Doxorubicin/pharmacology Gene Products, tat/chemistry Genes, Reporter Hela Cells Humans JNK Mitogen-Activated Protein Kinases/metabolism Luciferases/metabolism MAP Kinase Kinase 4 Mitogen-Activated Protein Kinase Kinases/metabolism Mitoxantrone/pharmacology Mutagens/*metabolism NF-kappa B/metabolism Peptides/*chemistry Plasmids/metabolism Protein Structure, Tertiary Transfection p38 Mitogen-Activated Protein Kinases/metabolism ras GTPase-Activating Proteins/*metabolism src Homology Domains
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 15:43
Dernière modification de la notice
08/05/2019 17:53
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