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该文献已被撤稿（Retracted Publication），引用前请核实。
PMID: 20233973 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Retracted Publication

The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo.

Blood ·Vol. 115 ·No. 22 ·2010-06-03 ·Pages 4478-87

Dasmahapatra G, Lembersky D, Kramer L, Fisher RI, Friedberg J, Dent P, Grant S

Abstract

Interactions between histone deacetylase inhibitors (HDACIs) and the novel proteasome inhibitor carfilzomib (CFZ) were investigated in GC- and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells. Coadministration of subtoxic or minimally toxic concentrations of CFZ) with marginally lethal concentrations of HDACIs (vorinostat, SNDX-275, or SBHA) synergistically increased mitochondrial injury, caspase activation, and apoptosis in both GC- and ABC-DLBCL cells. These events were associated with Jun NH2-terminal kinase (JNK) and p38MAPK activation, abrogation of HDACI-mediated nuclear factor-kappaB activation, AKT inactivation, Ku70 acetylation, and induction of gammaH2A.X. Genetic or pharmacologic JNK inhibition significantly diminished CFZ/vorinostat lethality. CFZ/vorinostat induced pronounced lethality in 3 primary DLBCL specimens but minimally affected normal CD34(+) hematopoietic cells. Bortezomib-resistant GC (SUDHL16) and ABC (OCI-LY10) cells exhibited partial cross-resistance to CFZ. However, CFZ/vorinostat dramatically induced resistant cell apoptosis, accompanied by increased JNK activation and gammaH2A.X expression. Finally, subeffective vorinostat doses markedly increased CFZ-mediated tumor growth suppression and apoptosis in a murine xenograft OCI-LY10 model. These findings indicate that HDACIs increase CFZ activity in GC- and ABC-DLBCL cells sensitive or resistant to bortezomib through a JNK-dependent mechanism in association with DNA damage and inhibition of nuclear factor-kappaB activation. Together, they support further investigation of strategies combining CFZ and HDACIs in DLBCL.

MeSH Terms
Animals Antineoplastic Agents/administration & dosage Apoptosis/drug effects Boronic Acids/pharmacology Bortezomib Cell Cycle/drug effects Chymotrypsin/antagonists & inhibitors DNA Damage Drug Resistance, Neoplasm Drug Synergism Histone Deacetylase Inhibitors/administration & dosage Humans Hydroxamic Acids/administration & dosage In Vitro Techniques JNK Mitogen-Activated Protein Kinases/metabolism Lymphoma, Large B-Cell, Diffuse/drug therapy,metabolism,pathology Mice Mice, Nude Mitochondria/drug effects NF-kappa B/metabolism Oligopeptides/administration & dosage Protease Inhibitors/administration & dosage Proteasome Inhibitors Pyrazines/pharmacology Vorinostat Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents Boronic Acids Histone Deacetylase Inhibitors Hydroxamic Acids NF-kappa B Oligopeptides Protease Inhibitors Proteasome Inhibitors Pyrazines Vorinostat Bortezomib carfilzomib JNK Mitogen-Activated Protein Kinases Chymotrypsin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Dasmahapatra Girija
Department of Medicine, Virginia Commonwealth University Health Systems, Richmond, VA 23298, USA.
Lembersky Dmitry
Kramer Lora
Fisher Richard I
Friedberg Jonathan
Dent Paul
Grant Steven
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2009-12-257261
Published
2010-06-03
Epub
2010-00-16
Pages
4478-87
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2881506
Subset
IM
Grants
NCI NIH HHS · 1P50 CA130805 · United States
NCI NIH HHS · CA63753 · United States
NCI NIH HHS · R01 CA100866 · United States
NCI NIH HHS · R01 CA063753 · United States
NCI NIH HHS · R01 CA093738 · United States
NCI NIH HHS · CA100866 · United States
NCI NIH HHS · P50 CA130805 · United States
NCI NIH HHS · R01 CA141703 · United States
NCI NIH HHS · CA93738 · United States
NIDDK NIH HHS · R01 DK052825 · United States
NCI NIH HHS · R01 CA150214 · United States
Corrections
CommentIn
PMID: 26693581
CommentIn
PMID: 27737268
RetractionIn
PMID: 31126919
External Links
PubMed source DOI: 10.1182/blood-2009-12-257261 PMC Full Text View journal details
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