Berberine exerts anti-tumor activity in diffuse large B-cell lymphoma by modulating c-myc/CD47 axis

  • Biochem Pharmacol. 2021 Jun;188:114576. doi: 10.1016/j.bcp.2021.114576.
Shuai Ren  1 ,  Yiqing Cai  1 ,  Shunfeng Hu  1 ,  Jiarui Liu  1 ,  Yi Zhao  1 ,  Mengfei Ding  1 ,  Xiaomin Chen  1 ,  Linquan Zhan  1 ,  Xiangxiang Zhou  2 ,  Xin Wang  3
Affiliations
  • 1. Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; School of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2. Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; School of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong 250021, China; Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong 250021, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 251006, China. Electronic address: [email protected].
  • 3. Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; School of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong 250021, China; Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong 250021, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 251006, China. Electronic address: [email protected].
PMID: 33930347 DOI: 10.1016/j.bcp.2021.114576
Abstract

Diffuse Large B-cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma (NHL) with high clinical heterogeneity and poor prognosis. Immune escape mediated by CD47 overexpression contributes to the limited efficacy of rituximab, an anti-CD20 antibody, which indicates a target to improve the efficacy of DLBCL treatment. Here, we validated berberine, a natural compound, as a suppressor of CD47 and revealed the involved mechanism and biological function in DLBCL. Berberine downregulated the expression of CD47 in DLBCL at the transcriptional level by suppressing c-Myc expression. Berberine-induced CD47 inhibition enhanced the phagocytosis of Macrophages, thereby eliminating DLBCL cells in vitro and in vivo. Interestingly, berberine enhanced the efficiency of anti-CD47 antibody and rituximab-mediated phagocytosis. Moreover, a novel prognostic model based on the combination of CD47 and CD68, a biomarker of Macrophages, was established in DLBCL. Our results highlighted for the first time that berberine could restore macrophage function in the tumor microenvironment, enhance rituximab-mediated phagocytosis and promote anti-CD47 antibody function via suppressing CD47 expression, which revealed a new anti-tumor mechanism of berberine and provided novel insights into the rituximab-based immunochemotherapy and CD47-targeted immunotherapy in DLBCL.

Keywords
Berberine; CD47; Diffuse large B-cell lymphoma; Immunochemotherapy; Phagocytosis.
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