title: Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma.
abstract: OBJECTIVE
  Mantle cell lymphoma (MCL) is an incurable disease with an aggressive course and novel treatment strategies are urgently needed. The purpose of this study was to evaluate the effects of histone deacetylase (HDAC) inhibitors, a new group of antiproliferative agents, on human MCL cells.
  
  
  METHODS
  Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8-72 h. Their effects on cell viability, apoptosis induction and cell cycle proliferation were studied. Moreover, the influence of SAHA on the expression of cyclin D1, the cell cycle regulators p21 and p27 and the production of vascular endothelial growth factor (VEGF) were analyzed.
  
  
  RESULTS
  The HDAC inhibitors induced accumulation of acetylated histones in MCL cells. MTT assays and Annexin-V staining showed that they potently inhibited viability in a dose-dependent manner and induced apoptosis in all cell lines tested. Cell cycle analysis indicated that their exposure to SAHA or NaB decreased the proportion of cells in S phase and increased the proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the two HDAC inhibitors resulted in downregulation of cyclin D1. SAHA lead to an upregulation of p21 in all cell lines and an upregulation of p27 in JeKo-1 and Granta-519 cells, while expression of p27 in Hbl-2 was not altered. In addition, SAHA inhibited the production of the angiogenic cytokine VEGF. Treatment with NaB increased the expression of p21 in JeKo-1 and Hbl-2 cells, while in Granta 519 cells no effect was noted. The expression of p27 remained constant in all three cell lines after exposure to NaB.
  
  
  CONCLUSIONS
  Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach.
authors.affiliation: Department of Hematology and Oncology, University Hospital Charité, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heider
authors.forename: Martin
authors.initials: M
authors.lastname: Kaiser
authors.forename: Jan
authors.initials: J
authors.lastname: Sterz
authors.forename: Ivana
authors.initials: I
authors.lastname: Zavrski
authors.forename: Christian
authors.initials: C
authors.lastname: Jakob
authors.forename: Claudia
authors.initials: C
authors.lastname: Fleissner
authors.forename: Jan
authors.initials: J
authors.lastname: Eucker
authors.forename: Kurt
authors.initials: K
authors.lastname: Possinger
authors.forename: Orhan
authors.initials: O
authors.lastname: Sezer
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000201:enzymology* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D000077337:Vorinostat
chemical_list: D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018809:Proliferating Cell Nuclear Antigen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C413374:p27 antigen; D019938:Cyclin D1; D000077337:Vorinostat; D006655:Histone Deacetylases