title: The HDAC inhibitor LBH589 enhances the antimyeloma effects of the IGF-1RTK inhibitor picropodophyllin.
abstract: OBJECTIVE
  We have previously shown the use of the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) as an attractive strategy to combat multiple myeloma (MM) in vitro and in vivo. After a combinatorial drug screening, the histone deacetylase inhibitor LBH589 was shown to act in synergy with PPP reducing survival of MM cells. In this study, we tried to elucidate the molecular mechanisms underlying this combinatorial effect.
  
  
  METHODS
  The in vitro anti-MM effects of PPP and LBH589 alone and in combination were evaluated by studying apoptosis, cell cycle distribution, and downstream transcriptome using both human MM cell lines and cells from the murine 5T3MM model. In vivo the effect on survival of 5T33MM-inoculated mice was evaluated.
  
  
  RESULTS
  In the human MM cell line RPMI8226, treatment with PPP and LBH589 in combination resulted in a five-fold increase of apoptosis, and an additive effect on the cleavage of the active forms of caspase-8 was observed as compared with the single drug treatments. Cell cycle analysis revealed an accumulation of cells in the G(2)-M phase and subsequent downregulation of cell cycle regulating proteins. These data were also confirmed in the 5T33MM cells in vitro. Also, the transcriptome was analyzed by Affymetrix arrays showing gene expression alterations mainly in categories of genes regulating apoptosis and cell adhesion. Combined treatment in vivo resulted in a significantly prolonged survival of 5T33MM-inoculated mice.
  
  
  CONCLUSIONS
  The results indicate an improved MM treatment opportunity in using a combination of PPP and LBH589.
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Belgium.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lemaire
authors.forename: Charlotte
authors.initials: C
authors.lastname: Fristedt
authors.forename: Prasoon
authors.initials: P
authors.lastname: Agarwal
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
authors.forename: Elke
authors.initials: E
authors.lastname: De Bruyne
authors.forename: Anders
authors.initials: A
authors.lastname: Österborg
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.forename: Ben
authors.initials: B
authors.lastname: Van Camp
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077767:Panobinostat; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D059467:Transcriptome / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C415032:picropodophyllin; D000077767:Panobinostat; D017526:Receptor, IGF Type 1; D053181:Caspase 8; D011034:Podophyllotoxin