Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Int J Mol Med. 2019 Jan;43(1):285-293. doi: 10.3892/ijmm.2018.3963. Epub 2018 Oct 29.
Research regarding histone deacetylase (HDAC) inhibitors (HDACis) has garnered interest for the treatment of multiple myeloma (MM). In addition, the high expression of nuclear factor (NF)‑κB in MM cells is considered an important factor in the occurrence and development of MM. The present study aimed to determine the short‑term effects of HDACis, chidamide and valproic acid (VPA), on MM cells, their effects on NF‑κB and the underlying mechanisms. The present study measured HDAC activity, and the proliferation and apoptosis of U266 and RPMI8226 MM cells following treatment with various concentrations of chidamide and VPA for 6 and 48 h. Western blotting was used to detect the expression levels of phosphorylated (p)‑IκB kinase (IKK)α/β, NF‑κB p65 and inhibitor of NF‑κB (IκBα) in U266 and RPMI8226 cells at various time points following treatment with chidamide and VPA (0, 2, 4 and 6 h). The results revealed that chidamide and VPA had no significant effect on the HDAC activity, proliferation and apoptosis of cells at 6 h; however, cell HDAC activity and proliferation were inhibited, and apoptosis was induced at 48 h. Furthermore, the expression levels of IκBα were gradually increased over time, whereas the expression levels of NF‑κB p65 gradually decreased. These findings indicated that long‑term (48 h) treatment with the HDACis chidamide and VPA inhibited the proliferation and promoted the apoptosis of MM cells; however, these HDACis had little effect on cell proliferation and apoptosis in the short term (6 h). Notably, in the short term (2‑6 h), hyperactivation of NF‑κB was inhibited via the IκBα‑NF‑κB p65 pathway. These findings indicated that cell growth may be inhibited and drug susceptibility may be promoted by blocking the NF‑κB pathway at an early stage, when HDACis are combined with other drugs in the treatment of MM.
关于组蛋白去乙酰化酶（HDAC）抑制剂（HDACis）的研究因其在多发性骨髓瘤（MM）治疗中的应用而受到关注。此外，MM 细胞中核因子（NF）-κB 的高表达被认为是 MM 发生和发展的一个重要因素。本研究旨在确定 HDACis 药物，即西达本胺和丙戊酸（VPA），对 MM 细胞的短期作用及其对 NF-κB 的影响和潜在机制。本研究测量了不同浓度的西达本胺和 VPA 处理 U266 和 RPMI8226 MM 细胞 6 和 48 小时后 HDAC 活性、增殖和凋亡情况。Western blot 法检测了 U266 和 RPMI8226 细胞在西达本胺和 VPA（0、2、4 和 6 小时）处理后不同时间点磷酸化（p）-IκB 激酶（IKK）α/β、NF-κB p65 和 NF-κB 抑制剂（IκBα）的表达水平。结果表明，西达本胺和 VPA 在 6 小时内对细胞的 HDAC 活性、增殖和凋亡没有显著影响；然而，在 48 小时时细胞的 HDAC 活性和增殖受到抑制，细胞凋亡被诱导。此外，IκBα的表达水平随时间逐渐增加，而 NF-κB p65 的表达水平逐渐降低。这些发现表明，长期（48 小时）使用 HDACis 西达本胺和 VPA 抑制 MM 细胞的增殖并促进其凋亡；然而，在短期内（6 小时），这些 HDACis 对细胞增殖和凋亡的影响较小。值得注意的是，在短期内（2-6 小时），通过 IκBα-NF-κB p65 通路抑制 NF-κB 的过度激活。这些发现表明，在早期阶段（当 HDACis 与其他药物联合用于治疗 MM 时），通过阻断 NF-κB 通路，可能会抑制细胞生长并促进药物敏感性。
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