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

Soo Jin Kim,Keon Wook Kang,U Ji Kim,Hae Yong Yoo,Yong June Choi

doi:10.3390/ijms21124377

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.

Highlights

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for approximately 30% of all lymphoma [1]
DLBCL can be further classified into activated B-cell (ABC)and germinal center-B cell (GCB)-DLBCL depending on the cellular origin
It is well established that acetylated histone proteins are regulated by histone deacetylase (HDAC) class I in the nucleus, and that acetylated tubulin is a target of HDAC class II in cytoplasm [17]

Summary

Introduction

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for approximately 30% of all lymphoma [1]. DLBCL can be further classified into activated B-cell (ABC)and germinal center-B cell (GCB)-DLBCL depending on the cellular origin. Of these two subtypes, patients with ABC-DLBCL have worse outcomes [2]. The standard chemotherapeutic regimen for DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). About 60–70% of patients are cured by R-CHOP therapy; the remaining 30–40% of patients respond poorly to standard therapy [3]. Among the patients who failed treatment with R-CHOP therapy, 20% suffered from primary refractory disease and 30% relapsed after achieving a complete response (CR) [4]. Patients who fail standard therapy have limited treatment options [5]

Methods

Results

Discussion

Conclusion