Document Detail


Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77-based mechanism.
MedLine Citation:
PMID:  19074726     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pan-histone deacetylase inhibitors, for example, vorinostat and panobinostat (LBH589; Novartis Pharmaceuticals, East Hanover, NJ), have shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, the molecular basis of this activity remains unclear. HDAC7, a class IIA histone deacetylase (HDAC), is overexpressed in thymocytes, where it represses expression of the proapoptotic nuclear orphan receptor Nur77. Here, we demonstrate that treatment with panobinostat rapidly inhibits the in vitro and intracellular activity, as well as the mRNA and protein levels of HDAC7, and induces expression and translocation of Nur77 to the mitochondria. There, Nur77 converts death resistance protein Bcl-2 into a killer protein, promoting cell death of cultured and patient-derived human CTCL cells. Treatment with panobinostat improved survival of athymic nude mice implanted with human CTCL cells. Ectopic expression of Nur77 induced apoptosis and sensitized HH cells to panobinostat, whereas combined knockdown of Nur77 and its family member Nor1 was necessary to inhibit panobinostat-induced apoptosis of CTCL cells. Cotreatment with the Bcl-2/Bcl-x(L) antagonist ABT-737 decreased resistance and synergistically induced apoptosis of human CTCL cells. These findings mechanistically implicate HDAC7 and Nur77 in sensitizing human CTCL cells to panobinostat as well as suggest that cotreatment with an anti-Bcl-2 agent would augment the anti-CTCL activity of panobinostat.
Authors:
Jianguang Chen; Warren Fiskus; Kelly Eaton; Pravina Fernandez; Yongchao Wang; Rekha Rao; Pearl Lee; Rajeshree Joshi; Yonghua Yang; Ravindra Kolhe; Ramesh Balusu; Prasanthi Chappa; Kavita Natarajan; Anand Jillella; Peter Atadja; Kapil N Bhalla
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Publication Detail:
Type:  Journal Article     Date:  2008-12-12
Journal Detail:
Title:  Blood     Volume:  113     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-04-24     Completed Date:  2009-05-08     Revised Date:  2011-10-13    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4038-48     Citation Subset:  AIM; IM    
Affiliation:
Medical College of Georgia Cancer Center, Augusta, GA 30912, USA.
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MeSH Terms
Descriptor/Qualifier:
Active Transport, Cell Nucleus
Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Biphenyl Compounds / pharmacology*
Cell Line, Tumor
DNA-Binding Proteins / genetics,  metabolism*
Female
Gene Expression Regulation, Neoplastic / drug effects
Histone Deacetylases / genetics,  metabolism*
Humans
Hydroxamic Acids / pharmacology*
Lymphoma, T-Cell, Cutaneous / genetics,  metabolism*,  pathology*
Membrane Transport Proteins / genetics,  metabolism
Mice
Mice, Nude
Mitochondria / drug effects,  metabolism
Nitrophenols / pharmacology*
Nuclear Receptor Subfamily 4, Group A, Member 1
Piperazines / pharmacology
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*,  metabolism
RNA Interference
Receptors, Steroid / genetics,  metabolism*
Substrate Specificity
Sulfonamides / pharmacology*
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/ABT-737; 0/Antineoplastic Agents; 0/Biphenyl Compounds; 0/DNA-Binding Proteins; 0/Hydroxamic Acids; 0/LBH589; 0/Membrane Transport Proteins; 0/NR4A1 protein, human; 0/Nitrophenols; 0/Nr4a1 protein, mouse; 0/Nuclear Receptor Subfamily 4, Group A, Member 1; 0/OSCP1 protein, human; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Steroid; 0/Sulfonamides; EC 3.5.1.98/HDAC7 protein, human; EC 3.5.1.98/Hdac7 protein, mouse; EC 3.5.1.98/Histone Deacetylases

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


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