Anti-Cancer Effects of CKD-581, a Potent Histone Deacetylase Inhibitor against Diffuse Large B-Cell Lymphoma.

Abstract

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-XL, 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.

• Authors: Soo Jin Kim, U Ji Kim, Hae Yong Yoo, Yong June Choi, Keon Wook Kang
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 12 (Jun 19 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32575557 (Publication Type: Journal Article)

Chemical References

• CKD-581
• Histone Deacetylase Inhibitors
• Histones
• MYC protein, human
• Organic Chemicals
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Tubulin

Topics

• Acetylation
• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Histones (metabolism)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, metabolism)
• Mice, SCID
• Organic Chemicals (administration & dosage, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Tubulin (metabolism)
• Xenograft Model Antitumor Assays