title: The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines.
abstract: 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 α 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.
authors.affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Lemoine
authors.forename: Enrico
authors.initials: E
authors.lastname: Derenzini
authors.forename: Daniela
authors.initials: D
authors.lastname: Buglio
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D000068338:Everolimus; D005434:Flow Cytometry; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles; D000077767:Panobinostat; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D051272:Glucose Transporter Type 1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051793:Hypoxia-Inducible Factor 1; D007166:Immunosuppressive Agents; D007211:Indoles; C495677:SLC2A1 protein, human; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077767:Panobinostat; D000068338:Everolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus