Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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CKD-581 Downregulates Wnt/β-Catenin Pathway by DACT3 Induction in Hematologic Malignancy

  • Kim, Soo Jin (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Kim, Suntae (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Choi, Yong June (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Kim, U Ji (CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation) ;
  • Kang, Keon Wook (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
  • Received : 2022.02.11
  • Accepted : 2022.05.20
  • Published : 2022.09.01
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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

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by Korean Government (2021R1A4A1021787).

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