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

  • Lei Zhang
  • Jiefeng Tong
  • Xin He
  • Yun Liang
  • Lei Zhu
  • Rongzhen Xu
  • Xiaoying Zhao
Original Article
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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

DLBCL c-Myc Small molecule inhibitor 4-Chlorobenzoyl berbamine 

Notes

Acknowledgements

This work was supported, in part, by Zhejiang Provincial Natural Science Foundation of China (Y18H160083).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of HematologyThe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
  2. 2.Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education)Zhejiang UniversityHangzhouChina

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