Kim Soo Jin, Kim Suntae, Choi Yong June, Kim U Ji, Kang Keon Wook
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation, Yongin 16995, Republic of Korea.
Biomol Ther (Seoul). 2022 Sep 1;30(5):435-446. doi: 10.4062/biomolther.2022.022. Epub 2022 Jul 4.
The present study evaluated the anti-cancer activity of histone deacetylase (HDAC)-inhibiting CKD-581 in multiple myeloma (MM) and its pharmacological mechanisms. CKD-581 potently inhibited a broad spectrum of HDAC isozymes. It concentration-dependently inhibited proliferation of hematologic cancer cells including MM (MM.1S and RPMI8226) and T cell lymphoma (HH and MJ). It increased the expression of the dishevelled binding antagonist of β-catenin 3 (DACT3) in T cell lymphoma and MM cells, and decreased the expression of c-Myc and β-catenin in MM cells. Additionally, it enhanced phosphorylated p53, p21, cleaved caspase-3 and the subG1 population, and reversely, downregulated cyclin D1, CDK4 and the anti-apoptotic BCL-2 family. Finally, administration of CKD-581 exerted a significant anti-cancer activity in MM.1S-implanted xenografts. Overall, CKD-581 shows anticancer activity via inhibition of the Wnt/β-catenin signaling pathway in hematologic malignancies. This finding is evidence of the therapeutic potential and rationale of CKD-581 for treatment of MM.
本研究评估了组蛋白去乙酰化酶（HDAC）抑制剂CKD - 581在多发性骨髓瘤（MM）中的抗癌活性及其药理机制。CKD - 581能有效抑制多种HDAC同工酶。它能浓度依赖性地抑制包括MM（MM.1S和RPMI8226）和T细胞淋巴瘤（HH和MJ）在内的血液癌细胞的增殖。它能增加T细胞淋巴瘤和MM细胞中β - 连环蛋白3（DACT3）的紊乱结合拮抗剂的表达，并降低MM细胞中c - Myc和β - 连环蛋白的表达。此外，它能增强磷酸化p53、p21、裂解的半胱天冬酶 - 3和亚G1期细胞群，相反地，下调细胞周期蛋白D1、细胞周期蛋白依赖性激酶4（CDK4）和抗凋亡BCL - 2家族。最后，给予CKD - 581在植入MM.1S的异种移植瘤中发挥了显著的抗癌活性。总体而言，CKD - 581通过抑制血液恶性肿瘤中的Wnt/β - 连环蛋白信号通路显示出抗癌活性。这一发现证明了CKD - 581治疗MM的治疗潜力和理论依据。
