Okabe Seiichi, Arai Yuya, Tanaka Yuko, Gotoh Akihiko
Department of Hematology, Tokyo Medical University, Tokyo, Japan.
Cancer Rep (Hoboken). 2025 Jun;8(6):e70249. doi: 10.1002/cnr2.70249.
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.
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.
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.
These findings highlight the potential of selinexor and venetoclax combination therapy to exploit hypoxia-induced vulnerabilities in MM cells.
多发性骨髓瘤（MM）是一种以浆细胞异常克隆生长为特征的血癌。缺氧在MM的进展和治疗耐药中起关键作用。
本研究调查B细胞/CLL淋巴瘤2（BCL2）家族基因的表达。我们还研究了BCL2和核输出蛋白1（XPO1）抑制剂的活性以及在缺氧条件下维奈克拉和塞利尼索的潜在治疗协同作用。
对公开可用数据集的分析显示，缺氧诱导BCL2和BCL2样蛋白11（BCL2L11）上调，而细胞死亡的BCL2相关激动剂（BAD）表达受到抑制。选择性BCL2抑制剂维奈克拉在缺氧条件下表现出增强的细胞毒性并增加了caspase-3/7活性。塞利尼索表现出强大的抗骨髓瘤作用，包括剂量依赖性降低细胞活力和增加凋亡活性。在缺氧条件下将塞利尼索与维奈克拉联合使用产生了抗骨髓瘤作用，显著降低细胞活力、增加凋亡并破坏线粒体膜电位。这种联合有效地克服了硼替佐米耐药的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。
这些发现突出了塞利尼索和维奈克拉联合治疗利用缺氧诱导的MM细胞脆弱性的潜力。
