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Ann Hematol. 2018 Dec;97(12):2353-2362. doi: 10.1007/s00277-018-3439-x. Epub 2018 Aug 11.

Novel synthetic 4-chlorobenzoyl berbamine inhibits c-Myc expression and induces apoptosis of diffuse large B cell lymphoma cells.

Author information

1
Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
2
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
3
Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. zrxyk10@zju.edu.cn.
4
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. zrxyk10@zju.edu.cn.
5
Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. zrxz@zju.edu.cn.

Abstract

C-Myc expression is associated with poor prognosis and aggressive progression of diffuse large B cell lymphoma (DLBCL), and the development of drug-like c-Myc inhibitors remains challenging. In this study, we report a novel berbamine derivative termed 4-chlorobenzoyl berbamine (CBBM) that potently induced the apoptosis of c-Myc-overexpressing DLBCL cells but spared normal blood cells. The compound showed IC50 values ranging from 1.93 to 3.89 μmol/L in DLCBL cells and exhibited a 4.75- to 9.64-fold increase in anti-tumor activity compared to berbamine. Additionally, CBBM inhibited the proliferation of the DLBCL line OCI-Ly3 cells through G0/G1 cell-cycle arrest and induced apoptosis. Further studies have shown that CBBM treatment leads to the proteasome-dependent degradation of c-Myc protein in OCI-Ly3 cells. Interestingly, we found that the inhibitory effect of CBBM was positively correlated with basal levels of CaMKIIγ, which is a key inducer of c-Myc expression in DLBCL cells. We also observed that CBBM inhibits the JAK2/STAT3 pathway, leading to reduced c-Myc transcription. Collectively, these findings suggest that CBBM could be a promising lead compound for treatment of c-Myc-driven DLBCL.

KEYWORDS:

4-Chlorobenzoyl berbamine; DLBCL; Small molecule inhibitor; c-Myc

PMID:
30099568
DOI:
10.1007/s00277-018-3439-x
[Indexed for MEDLINE]

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