Neoplasma. 2017;64(2):228-237. doi: 10.4149/neo_2017_209.
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.
在本研究中，我们分析了组蛋白去乙酰化酶抑制剂（HDACi）丙戊酸（VPA）和 SAHA 对人浆细胞白血病（PCL）细胞系 UHKT-944 在骨髓微环境（BMM）中的作用。为此，将细胞单独培养，与骨髓基质细胞（BMSCs）、细胞外基质（ECM）成分或白细胞介素-6 一起培养，并以不同浓度的 SAHA 和 VPA 处理 24/48 小时。为了研究 HDACi 的作用，我们研究了细胞增殖、凋亡、细胞周期和选定信号通路的变化。结果发现，SAHA 和 VPA 均诱导细胞凋亡，但对 UHKT-944 细胞的细胞周期分布没有影响。研究 SAHA 和 VPA 的抗增殖作用发现，BMSCs 和高浓度白细胞介素-6 对 SAHA 或两种抑制剂分别具有部分保护作用。未观察到 ECM 成分对 HDACi 效率的影响。进一步揭示 VPA 下调 STAT3 磷酸化，而两种抑制剂均降低 Akt 磷酸化。总之，VPA 和 SAHA 可能代表 PCL 治疗的另一种治疗策略。在研究针对浆细胞疾病的潜在治疗药物时，应考虑骨髓微环境的保护作用。
