Tang Sishi, Cheng Bingqing, Zhe Nana, Ma Dan, Xu Jibing, Li Xinyao, Guo Yongling, Wu Weibing, Wang Jishi
Guizhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University.
School of Clinical Medicine, Guizhou Medical University, Guizhou.
Anticancer Drugs. 2018 Jan;29(1):61-74. doi: 10.1097/CAD.0000000000000568.
Multiple myeloma (MM) is a hematological malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of molecular targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138 mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, especially the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clinical use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematological malignancies.
多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，其特征是骨髓中浆细胞的克隆性扩增。组蛋白去乙酰化酶（HDACs）代表了一种针对不同类型癌症的新型分子靶向治疗方法，也是骨髓瘤治疗的有前景的靶点。我们发现，MM患者CD138单核细胞中的HDAC3 mRNA和蛋白水平高于健康供体。因此，我们研究了新型I类HDAC抑制剂BG45对MM细胞的体外作用。当MM细胞中I类HDACs减少时，BG45下调血红素加氧酶1（HO-1）。HO-1是MM治疗的一个靶点。此外，BG45诱导组蛋白H3的高乙酰化，并抑制MM细胞系的生长，尤其是凋亡。BG45处理通过下调bcl-2和Bcl-xl、上调Bax和其他抗凋亡蛋白并激活聚（ADP-核糖）聚合酶，以及降低p-JAK2和p-STAT3的蛋白水平来诱导凋亡。这些作用部分被HO-1阻断。相应地，BG45导致细胞在G0/G1期积累，同时伴有CDK4和磷酸化视网膜母细胞瘤蛋白水平降低、p21水平升高以及CDK2水平适度降低。由于毒副作用和耐药性，单一药物的临床应用受到限制。然而，BG45与来那度胺联合使用具有协同作用。总之，我们验证了这种新型HDAC抑制剂的强效抗骨髓瘤活性，并且BG45与来那度胺联合是MM治疗的一种新方法。因此，BG45可能适用于MM和其他血液系统恶性肿瘤的治疗。
