PMID- 22408261
OWN - NLM
STAT- MEDLINE
DCOM- 20120712
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 119
IP  - 17
DP  - 2012 Apr 26
TI  - The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with 
      everolimus in Hodgkin lymphoma cell lines.
PG  - 4017-25
LID - 10.1182/blood-2011-01-331421 [doi]
AB  - The pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to 
      have significant clinical activity in patients with relapsed Hodgkin lymphoma, 
      but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, 
      we demonstrate that panobinostat has potent antiproliferative activity against 
      Hodgkin lymphoma-derived cell lines. At the molecular level, panobinostat 
      activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and 
      down-regulated hypoxia-inducible factor 1 alpha and its downstream targets, glucose 
      transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, 
      panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to 
      activation of mammalian target of rapamycin (mTOR) that promotes survival. 
      Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited 
      panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative 
      effects. Collectively, our data demonstrate that panobinostat is a potent 
      deacetylase inhibitor against Hodgkin lymphoma-derived cell lines, and provide a 
      mechanistic rationale for combining panobinostat with mTOR inhibitors for 
      treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on 
      GLUT1 expression suggests that panobinostat may modulate the results of clinical 
      diagnostic imaging tests that depend of functional GLUT1, such as 
      fluorodeoxyglucose positron emission tomography.
FAU - Lemoine, Manuela
AU  - Lemoine M
AD  - Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer 
      Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
FAU - Derenzini, Enrico
AU  - Derenzini E
FAU - Buglio, Daniela
AU  - Buglio D
FAU - Medeiros, L Jeffrey
AU  - Medeiros LJ
FAU - Davis, R Eric
AU  - Davis RE
FAU - Zhang, Jiexin
AU  - Zhang J
FAU - Ji, Yuan
AU  - Ji Y
FAU - Younes, Anas
AU  - Younes A
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - P50 CA136411/CA/NCI NIH HHS/United States
GR  - CA016672/CA/NCI NIH HHS/United States
GR  - 1P50CA136411-01A1/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120309
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Glucose Transporter Type 1)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Indoles)
RN  - 0 (SLC2A1 protein, human)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (STAT6 Transcription Factor)
RN  - 0 (STAT6 protein, human)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 9647FM7Y3Z (Panobinostat)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Apoptosis/*drug effects
MH  - Blotting, Western
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Chemokines/metabolism
MH  - Cytokines/metabolism
MH  - Drug Synergism
MH  - Everolimus
MH  - Flow Cytometry
MH  - Glucose Transporter Type 1/metabolism
MH  - Histone Deacetylase Inhibitors/pharmacology
MH  - Hodgkin Disease/*drug therapy/metabolism/*pathology
MH  - Humans
MH  - Hydroxamic Acids/*pharmacology
MH  - Hypoxia-Inducible Factor 1/metabolism
MH  - Immunosuppressive Agents/*pharmacology
MH  - Indoles
MH  - Panobinostat
MH  - Phosphorylation/drug effects
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - STAT5 Transcription Factor/metabolism
MH  - STAT6 Transcription Factor/metabolism
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Vascular Endothelial Growth Factor A/metabolism
PMC - PMC3350366
EDAT- 2012/03/13 06:00
MHDA- 2012/07/13 06:00
PMCR- 2013/04/26
CRDT- 2012/03/13 06:00
PHST- 2012/03/13 06:00 [entrez]
PHST- 2012/03/13 06:00 [pubmed]
PHST- 2012/07/13 06:00 [medline]
PHST- 2013/04/26 00:00 [pmc-release]
AID - S0006-4971(20)47962-5 [pii]
AID - 2011/331421 [pii]
AID - 10.1182/blood-2011-01-331421 [doi]
PST - ppublish
SO  - Blood. 2012 Apr 26;119(17):4017-25. doi: 10.1182/blood-2011-01-331421. Epub 2012 
      Mar 9.