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<p>High-grade B-cell lymphoma with concurrent MYC and BCL2/BCL6 rearrangements (HGBL-DHL) is a challenging disease resistant to front-line immunochemotherapies, which urgently requires novel therapeutic approaches. Herein, combination of chidamide and anlotinib demonstrated potential synergistic anti-lymphoma effects against HGBL-DHL. The cooperative effect of cell proliferation inhibition, apoptosis induction, and cell cycle arrest were demonstrated in cell lines through Cell Counting Kit-8, Annexin V/PI staining, and PI staining respectively. Moreover, in an HGBL-DHL-xenografted mouse model, the combination therapy markedly reduced tumor burden without inducing fatal toxicity. Mechanistically, chidamide suppressed HDAC3, while anlotinib inhibited VEGFR2, both leading to down-regulation of the PI3K/AKT signaling cascade. This dual suppression occurred as a result of their synergistic interaction. Downstream targets of the PI3K/AKT signaling pathway including proliferation-associated protein c-Myc, anti-apoptotic proteins BCL2 and MCL1, and cell cycle-associated protein cyclin A2 were all synergistically down-regulated, which coincided with the phenotypic outcomes. Collectively, our preclinical findings underscored the synergistic activity of chidamide and anlotinib combination against HGBL-DHL, warranting further clinical evaluation of this regimen for treating this challenging entity.</p>

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Chidamide and anlotinib synergistically inhibit high grade B-cell lymphomas via PI3K/AKT signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Jiazhen Lin,
  • Xinguo Zhuang,
  • Shuman Jia,
  • Hui Zhou,
  • Dongmei Qin,
  • Jie Zhou,
  • Yiming Luo,
  • Bing Xu,
  • Jie Zha

摘要

High-grade B-cell lymphoma with concurrent MYC and BCL2/BCL6 rearrangements (HGBL-DHL) is a challenging disease resistant to front-line immunochemotherapies, which urgently requires novel therapeutic approaches. Herein, combination of chidamide and anlotinib demonstrated potential synergistic anti-lymphoma effects against HGBL-DHL. The cooperative effect of cell proliferation inhibition, apoptosis induction, and cell cycle arrest were demonstrated in cell lines through Cell Counting Kit-8, Annexin V/PI staining, and PI staining respectively. Moreover, in an HGBL-DHL-xenografted mouse model, the combination therapy markedly reduced tumor burden without inducing fatal toxicity. Mechanistically, chidamide suppressed HDAC3, while anlotinib inhibited VEGFR2, both leading to down-regulation of the PI3K/AKT signaling cascade. This dual suppression occurred as a result of their synergistic interaction. Downstream targets of the PI3K/AKT signaling pathway including proliferation-associated protein c-Myc, anti-apoptotic proteins BCL2 and MCL1, and cell cycle-associated protein cyclin A2 were all synergistically down-regulated, which coincided with the phenotypic outcomes. Collectively, our preclinical findings underscored the synergistic activity of chidamide and anlotinib combination against HGBL-DHL, warranting further clinical evaluation of this regimen for treating this challenging entity.