Document Detail

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells.
MedLine Citation:
PMID:  19421231     Owner:  NLM     Status:  MEDLINE    
p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein-Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10-20% of sporadic cases. In EBV(-) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(-) or latency I EBV(+) cells, whereas latency III EBV(+) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(-) or latency I EBV(+) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV(+) cells. p21(WAF1) which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21(WAF1) restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21(WAF1)-mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients.
B Renouf; E Hollville; A Pujals; C Tétaud; J Garibal; J Wiels
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-05-07
Journal Detail:
Title:  Leukemia     Volume:  23     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-09     Completed Date:  2009-09-23     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1557-63     Citation Subset:  IM    
UMR 8126 CNRS, Univ Paris-Sud, Institut Gustave Roussy, Villejuif, France.
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MeSH Terms
Apoptosis / drug effects*
Burkitt Lymphoma / drug therapy*,  pathology,  virology
Cell Cycle / drug effects
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / physiology
Drug Resistance, Neoplasm
Etoposide / pharmacology
Herpesvirus 4, Human / isolation & purification*
Imidazoles / pharmacology*
Piperazines / pharmacology*
Poly(ADP-ribose) Polymerases / metabolism
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Tumor Suppressor Protein p53 / physiology*
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Imidazoles; 0/Piperazines; 0/Tumor Suppressor Protein p53; 0/nutlin 3; 33419-42-0/Etoposide; EC Polymerases; EC protein, human; EC Proteins c-mdm2

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