Document Detail

Doxorubicin coupled to penetratin promotes apoptosis in CHO cells by a mechanism involving c-Jun NH2-terminal kinase.
MedLine Citation:
PMID:  20457128     Owner:  NLM     Status:  MEDLINE    
Doxorubicin (Dox) has demonstrated potent activity in treating malignant lymphomas but its therapeutic efficacy is hampered by induction of cardiotoxicity. This side effect is related to the ability of the drug to generate reactive oxygen species in cells. Previously, we demonstrated that coupling Dox to penetratin (Pen), a cell penetrating peptide, represent a valuable strategy to overcome drug resistance in CHO cells. In the present study, we evaluated the consequences of the conjugation of Dox to Pen in term of apoptosis induction. When tested on CHO cells, Dox-Pen generated a typical apoptotic phenotype but at lower dose that needed for unconjugated Dox. Cell death induction was associated with chromatin condensation, caspase activation, Bax oligomerisation and release of cytochrome c. By using reactive oxygen species and c-jun NH2-terminal kinase (JNK) inhibitors, we prevented Dox- and Dox-Pen-induced CHO cell death. The chimeric soluble DR5 receptor that inhibits TRAIL induced cell death does not prevent Dox or Dox-Pen-induced cytotoxicity. These observations indicate that conjugation of Dox to cell penetrating peptide does not impair the ability of the drug to trigger cell death through activation of the intrinsic pathway involving c-Jun NH2-terminal kinase but could exhibit less toxic side effects and could warrant its use in clinic.
Sonia Aroui; Donia Mili; Souhir Brahim; Michel De Waard; Abderraouf Kenani
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Publication Detail:
Type:  Journal Article     Date:  2010-05-10
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  396     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-14     Completed Date:  2010-07-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  908-14     Citation Subset:  IM    
Copyright Information:
(c) 2010 Elsevier Inc. All rights reserved.
Unité 05/UR/09-09, Mécanismes Moléculaires et Pathologies, Faculté de Médecine de Monastir, 5019 Monastir, Tunisia.
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MeSH Terms
Antibiotics, Antineoplastic / metabolism,  pharmacology*
CHO Cells
Carrier Proteins / metabolism,  pharmacology*
Doxorubicin / metabolism,  pharmacology*
JNK Mitogen-Activated Protein Kinases / metabolism*
Reactive Oxygen Species / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Carrier Proteins; 0/Reactive Oxygen Species; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/penetratin; 23214-92-8/Doxorubicin; EC Mitogen-Activated Protein Kinases

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