Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.022
CKD-581 Downregulates Wnt/β-Catenin Pathway by DACT3 Induction in Hematologic Malignancy
Soo Jin Kim1,2, Suntae Kim1, Yong June Choi1, U Ji Kim2 and Keon Wook Kang1,*
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826,
2CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation, Yongin 16995, Republic of Korea
*E-mail: kwkang@snu.ac.kr
Tel: +82-2-2880-7851, Fax: +82-2-2872-1795
Received: February 11, 2022; Revised: May 10, 2022; Accepted: May 20, 2022; Published online: July 4, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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.
Keywords: CKD-581, DACT3, HDAC, Wnt/β-catenin pathway, Hematologic cancer


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