Document Detail


Restoration of p53 pathway by nutlin-3 induces cell cycle arrest and apoptosis in human rhabdomyosarcoma cells.
MedLine Citation:
PMID:  19509161     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Seventy to eighty percent of rhabdomyosarcoma (RMS) tumors retain wild-type p53. The tumor suppressor p53 plays a central role in inducing cell cycle arrest or apoptosis in response to various stresses. p53 protein levels are regulated by MDM2 through ubiquitin-dependent degradation. In this study, we evaluated whether nutlin-3, a recently developed small-molecule antagonist of MDM2, has an effect on p53-dependent cell cycle arrest and apoptosis in cultured human RMS cell lines. EXPERIMENTAL DESIGN: Five RMS cell lines with different p53 statuses and MDM2 expression levels were treated with nutlin-3. Gene expression patterns, cell viability, cell cycle, and apoptosis after nutlin-3 treatment, and antitumor activity of combination treatment with vincristine or actinomycin D were assessed. RESULTS: Significant p53 activation was observed in wild-type p53 cell lines after nutlin-3 treatment. p53 activation led to cell cycle arrest in parallel with increased p21 expression. Furthermore, these cell lines underwent p53-dependent apoptosis, concomitant with elevation of proapoptotic genes and activation of caspase-3. The effect of nutlin-3 was almost the same in terms of half maximal inhibitory concentration and apoptosis whether or not MDM2 was overexpressed. Nutlin-3 did not induce either cell cycle arrest or apoptosis in p53 mutant cell lines. A combination of vincristine or actinomycin D with nutlin-3 enhanced the antitumor activity in RMS cell lines with wild-type p53. CONCLUSIONS: Nutlin-3 effectively restored p53 function in both normal MDM2 expression and MDM2 overexpression RMS cell lines with wild-type p53. p53 restoration therapy is a potential therapeutic strategy for refractory RMS with wild-type p53.
Authors:
Mitsuru Miyachi; Naoki Kakazu; Shigeki Yagyu; Yoshiki Katsumi; Satoko Tsubai-Shimizu; Ken Kikuchi; Kunihiko Tsuchiya; Tomoko Iehara; Hajime Hosoi
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-06-09
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  15     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-16     Completed Date:  2009-09-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4077-84     Citation Subset:  IM    
Affiliation:
Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / pharmacology*
Apoptosis*
Cell Cycle / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects,  physiology
Dactinomycin / pharmacology
Drug Synergism
Humans
Imidazoles / pharmacology*
Mutation, Missense / genetics
Neoplasms, Muscle Tissue / metabolism*
Piperazines / pharmacology*
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Rhabdomyosarcoma / metabolism*
Tumor Suppressor Protein p53 / agonists,  genetics,  metabolism*
Vincristine / pharmacology
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Imidazoles; 0/Piperazines; 0/Tumor Suppressor Protein p53; 0/nutlin 3; 50-76-0/Dactinomycin; 57-22-7/Vincristine; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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