Document Detail


Induction of cell cycle arrest and DNA damage by the HDAC inhibitor panobinostat (LBH589) and the lipid peroxidation end product 4-hydroxynonenal in prostate cancer cells.
MedLine Citation:
PMID:  21078383     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Histone deacetylase inhibitors (HDACIs) are promising antineoplastic agents for the treatment of cancer. Here we report that the lipid peroxidation end product 4-hydroxynonenal (HNE) significantly potentiates the anti-tumor effects of the HDAC inhibitor panobinostat (LBH589) in the PC3 prostate cancer cell model. Panobinostat and HNE inhibited proliferation of PC3 cells and the combination of the two agents resulted in a significant combined effect. Cell cycle analysis revealed that both single agents and, to a greater extent, their combined treatment induced G2/M arrest, but cell death occurred in the combined treatment only. Furthermore, HNE and, to a greater extent, the combined treatment induced dephosphorylation of Cdc2 leading to progression into mitosis as confirmed by α-tubulin/DAPI staining and phospho-histone H3 (Ser10) analysis. To evaluate possible induction of DNA damage we utilized the marker phosphorylated histone H2A.X. Results showed that the combination of panobinostat and HNE induced significant DNA damage concomitant with the mitotic arrest. Then, by using androgen receptor (AR)-expressing PC3 cells we observed that the responsiveness to HNE and panobinostat was independent of the expression of functional AR. Taken together, our data suggest that HNE potentiates the antitumoral effect of the HDACI panobinostat in prostate cancer cells.
Authors:
Piergiorgio Pettazzoni; Stefania Pizzimenti; Cristina Toaldo; Paula Sotomayor; Luigina Tagliavacca; Song Liu; Dan Wang; Rosalba Minelli; Leigh Ellis; Peter Atadja; Eric Ciamporcero; Mario Umberto Dianzani; Giuseppina Barrera; Roberto Pili
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-13
Journal Detail:
Title:  Free radical biology & medicine     Volume:  50     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  313-22     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, Turin, Italy.
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Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
P50 CA58236/CA/NCI NIH HHS

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