Therapeutic Potential of Venetoclax and Selinexor in Targeting Hypoxia-Induced Vulnerabilities in Multiple Myeloma

IF 1.9 Q4 ONCOLOGY

Cancer reports Pub Date : 2025-06-20 DOI:10.1002/cnr2.70249

Seiichi Okabe, Yuya Arai, Yuko Tanaka, Akihiko Gotoh

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Abstract

Background

Multiple myeloma (MM) is a blood cancer marked by the abnormal clonal growth of plasma cells. Hypoxia plays a critical role in the progression and treatment resistance of MM.

Aims

This study investigates the expression of B-cell/CLL lymphoma 2 (BCL2) family genes. We also investigated the activity of BCL2 and exportin-1 (XPO1) inhibitors and the potential therapeutic synergy of venetoclax and selinexor under hypoxic conditions.

Methods and Results

Analysis of publicly available datasets revealed hypoxia-induced upregulation of BCL2 and BCL2-like 11 (BCL2L11), while BCL2-associated agonist of cell death (BAD) expression was suppressed. Venetoclax, a selective BCL2 inhibitor, demonstrated enhanced cytotoxicity and increased caspase-3/7 activity under hypoxic conditions. Selinexor exhibited potent anti-myeloma effects, including dose-dependent reductions in cell viability and increased apoptotic activity. Combining selinexor with venetoclax under hypoxia produced anti-myeloma effects, significantly reducing cell viability, increasing apoptosis, and disrupting the mitochondrial membrane potential. This combination effectively overcame resistance in bortezomib-resistant MM cells and demonstrated efficacy in primary plasma cell leukemia (PCL) samples.

Conclusion

These findings highlight the potential of selinexor and venetoclax combination therapy to exploit hypoxia-induced vulnerabilities in MM cells.

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Venetoclax和Selinexor靶向缺氧诱导的多发性骨髓瘤的治疗潜力

背景：多发性骨髓瘤（Multiple myeloma， MM）是一种以浆细胞克隆生长异常为特征的血癌。缺氧在MM的进展和治疗耐药中起关键作用。目的研究b细胞/CLL淋巴瘤2 （BCL2）家族基因的表达。我们还研究了BCL2和输出素-1 （XPO1）抑制剂的活性以及venetoclax和selinexor在缺氧条件下的潜在治疗协同作用。方法和结果对公开数据集的分析显示，缺氧诱导BCL2和BCL2样11 （BCL2L11）上调，而BCL2相关的细胞死亡激动剂（BAD）表达被抑制。Venetoclax是一种选择性BCL2抑制剂，在缺氧条件下显示出增强的细胞毒性和增加的caspase-3/7活性。Selinexor表现出强大的抗骨髓瘤作用，包括剂量依赖性的细胞活力降低和凋亡活性增加。在缺氧条件下，selinexor联合venetoclax具有抗骨髓瘤作用，显著降低细胞活力，增加细胞凋亡，破坏线粒体膜电位。这种组合有效地克服了对硼替佐米耐药的MM细胞的耐药性，并在原发性浆细胞白血病（PCL）样本中显示出疗效。结论selinexor和venetoclax联合治疗具有利用缺氧诱导的MM细胞脆弱性的潜力。

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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