College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.
CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation, Gyeonggi-do 16995, Korea.
Int J Mol Sci. 2020 Jun 19;21(12):4377. doi: 10.3390/ijms21124377.
Double-hit lymphoma (DHL) and double-expressor lymphoma (DEL) are aggressive forms of lymphoma that require better treatments to improve patient outcomes. CKD-581 is a new histone deacetylase (HDAC) inhibitor that exhibited a better safety profile in clinical trials compared to other HDAC inhibitors. Here, we demonstrate that CKD-581 inhibited the class I-II HDAC family via histone H3 and tubulin acetylation. CKD-581 treatment also up-regulated the phosphorylation of histone H2AX (γH2AX, DNA double-strand break marker), and reduced levels of MYC and anti-apoptotic proteins such as BCL-2, BCL-6, BCL-L, and MCL-1 in DH/DE-diffuse large B cell lymphoma (DLBCL) cell lines. Ultimately, CKD-581 also induced apoptosis via poly(ADP ribose) polymerase 1 (PARP1) cleavage. In a DLBCL SCID mouse xenograft model, CKD-581 exhibited anti-cancer effects comparable with those of rituximab (CD20 mAb). Our findings suggest that CKD-581 could be a good candidate for the treatment of DLBCL.
双打击淋巴瘤（DHL）和双表达淋巴瘤（DEL）是侵袭性淋巴瘤，需要更好的治疗方法来改善患者的预后。CKD-581 是一种新型组蛋白去乙酰化酶（HDAC）抑制剂，与其他 HDAC 抑制剂相比，在临床试验中表现出更好的安全性。在这里，我们证明 CKD-581 通过组蛋白 H3 和微管蛋白乙酰化抑制 I 类-II 类 HDAC 家族。CKD-581 治疗还上调了组蛋白 H2AX（γH2AX，DNA 双链断裂标志物）的磷酸化，并降低了 DH/DE 弥漫性大 B 细胞淋巴瘤（DLBCL）细胞系中 MYC 和抗凋亡蛋白（如 BCL-2、BCL-6、BCL-L 和 MCL-1）的水平。最终，CKD-581 还通过聚（ADP 核糖）聚合酶 1（PARP1）切割诱导细胞凋亡。在 DLBCL SCID 小鼠异种移植模型中，CKD-581 表现出与利妥昔单抗（CD20 mAb）相当的抗癌作用。我们的研究结果表明，CKD-581 可能是治疗 DLBCL 的一个很好的候选药物。
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