title: Histone deacetylase inhibitors in plasma cell leukemia treatment: effect of bone marrow microenvironment.
abstract: In the presented study we analysed the effect of histone deacetylase inhibitors (HDACi) suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) on human plasma cell leukemia (PCL) cell line UHKT-944 in the presence of bone marrow microenvironment (BMM). For the analysis, the cells were cultured alone, with bone marrow stromal cells (BMSCs), with extracellular matrix (ECM) components or with interleukin-6, and treated with varied concentrations of SAHA and VPA for 24/48 hours. To study the effect of HDACi, we investigated cell proliferation, apoptosis, cell cycle and changes in selected signalling pathways. We found that both SAHA and VPA induced apoptosis, but had no effect on the cell cycle distribution of UHKT-944 cells. Investigation of the antiproliferative effect of SAHA and VPA revealed that BMSCs and high concentration of interleukin-6 had partial protective effect against SAHA or both inhibitors, respectively. No effect of ECM components on the efficiency of HDACi was observed. We further revealed that VPA down-regulated STAT3 phosphorylation while both inhibitors decreased Akt phosphorylation. In conclusion, VPA and SAHA might represent an additional therapeutic strategy in the PCL treatment. Protective effect of BMM should be taken into account when investigating prospective therapeutic agents against plasma cell disorders.
authors.forename: I
authors.initials: I
authors.lastname: Burianova
authors.forename: K
authors.initials: K
authors.lastname: Kuzelova
authors.forename: O
authors.initials: O
authors.lastname: Mitrovsky
authors.forename: I
authors.initials: I
authors.lastname: Spicka
authors.forename: P
authors.initials: P
authors.lastname: Stockbauer
authors.forename: M
authors.initials: M
authors.lastname: Zackova
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001853:Bone Marrow; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids; D015850:Interleukin-6 / Q000378:metabolism; D007952:Leukemia, Plasma Cell / Q000188:drug therapy / Q000473:pathology*; D011446:Prospective Studies; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077337:Vorinostat; D014635:Valproic Acid
keywords: bone marrow microenvironment; drug resistance; histone deacetylase inhibitors; multiple myeloma plasma cell leukemia.