Combined Inhibition of XPO1 and DNA Methylation Exerts Synergistic Effects in DLBCL.

IF 3 2区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Carcinogenesis Pub Date : 2025-07-13 DOI:10.1002/mc.70014

Qi Li, Xiaofeng Xue, Si Chen, Xinyun Zhang, Yuchen Zhang, Ruijing Hu, Xinyuan Zhang, Linlin Qin, Menglu Chen, Wenzhuo Zhuang, Bingzong Li

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引用次数: 0

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma characterized by high rates of relapse and limited responsiveness to standard chemotherapy. Selinxor, a selective inhibitor of XPO1, exhibited antitumor activity in various cancers. However, clinical trial results revealed that selinexor monotherapy exhibited unsatisfactory efficacy in DLBCL. Our study indicated that XPO1 expression was increased in DLBCL and was correlated with poor outcomes of DLBCL patients. Comprehensive proteomic and transcriptomics analysis showed that selinexor has significant impacts on various biological processes in DLBCL. Furthermore, we explored combination strategies involving selinexor to enhance DLBCL treatment. We examined the combined effects of selinexor with decitabine (DAC) and lenalidomide (LEN), and found that selinexor exhibited a synergistic effect with DAC against DLBCL. Further analysis revealed that DAC exerted a synergistic antitumor effect with selinexor by reversing the DNMT1 expression and DNA methylation alterations induced by selinexor. Overall, these findings provided valuable insights into the global impact of selinexor on DLBCL. The combination therapy of selinexor and DAC emerges as a highly promising strategy for effectively treating DLBCL, holding great potential for clinical application.

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XPO1和DNA甲基化联合抑制在DLBCL中发挥协同作用。

弥漫性大b细胞淋巴瘤（DLBCL）是一种侵袭性非霍奇金淋巴瘤，其特点是复发率高，对标准化疗的反应有限。Selinxor是XPO1的选择性抑制剂，在多种癌症中显示出抗肿瘤活性。然而，临床试验结果显示，塞利那索单药治疗DLBCL的疗效并不理想。我们的研究表明，XPO1在DLBCL中表达升高，并与DLBCL患者预后不良相关。综合蛋白质组学和转录组学分析表明，selinexor对DLBCL的多种生物学过程有显著影响。此外，我们探索了包括塞利纳索在内的联合策略，以加强DLBCL的治疗。我们研究了selinexor与地西他滨（DAC）和来那度胺（LEN）的联合作用，发现selinexor与DAC对DLBCL有协同作用。进一步分析发现，DAC通过逆转selinexor诱导的DNMT1表达和DNA甲基化改变，与selinexor发挥协同抗肿瘤作用。总的来说，这些发现为selinexor对DLBCL的全球影响提供了有价值的见解。selinexor与DAC联合治疗是一种非常有前景的有效治疗DLBCL的策略，具有很大的临床应用潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Carcinogenesis 医学-生化与分子生物学

CiteScore

7.30

自引率

2.20%

发文量

112

审稿时长

2 months

期刊介绍： Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.