Department of Pathology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China.
Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China.
Technol Cancer Res Treat. 2023 Jan-Dec;22:15330338231208608. doi: 10.1177/15330338231208608.
Mantle cell lymphoma (MCL) can be stratified into blastoid and classical subtypes based on morphological features, with the former subtype having a poorer prognosis. Despite recent advances in targeted approaches, including multiple bruton tyrosine kinase inhibitors which yield impressive clinical responses and improve prognoses, MCL remains an incurable disease with frequent relapses. Additional therapeutic interventions are therefore unmet medical needs for the management of patients with MCL. Cell viability and apoptosis assays were employed to analyze the therapeutic interaction of venetoclax combined with selinexor in MCL cells. Western blot was used to investigate the potential mechanism of action for the synergy of venetoclax in combination with selinexor in MCL cells. In this study, we revealed that both blastoid and classical MCL cells were vulnerable to the cytotoxic effects of selinexor, a well-established XPO1 inhibitor, manifested by loss of cell viability and induction of cell apoptosis. Moreover, our data indicated that the addition of venetoclax to selinexor showed synergistically decreased cell viabilities and increased cell deaths in blastoid and classical MCL cells compared to each single drug treatment. Either selinexor or venetoclax treatment alone decreased MCL1 expressions and increased BAX levels in MCL cells, and these effects were further enhanced by their combined regimen. Mechanistically, our findings demonstrated that induction of DNA damage and inactivation of DNA damage response were involved in the synergistic interaction of the drug combination regimen. Collectively, this study might provide a potential attractive therapy option for the treatment of MCL. However, the conclusion needs additional experimental validation in in vivo models and clinical evaluations are mandatory.
套细胞淋巴瘤（MCL）可以根据形态学特征分为母细胞样和经典亚型，前者亚型预后较差。尽管最近在靶向治疗方面取得了进展，包括多种布鲁顿酪氨酸激酶抑制剂，它们产生了令人印象深刻的临床反应并改善了预后，但 MCL 仍然是一种无法治愈的疾病，经常复发。因此，对于 MCL 患者的治疗，需要额外的治疗干预措施来满足未满足的医疗需求。采用细胞活力和细胞凋亡检测分析 Venetoclax 联合 Selinexor 在 MCL 细胞中的治疗相互作用。Western blot 用于研究 Venetoclax 与 Selinexor 联合在 MCL 细胞中协同作用的潜在作用机制。在这项研究中，我们揭示了母细胞样和经典 MCL 细胞都容易受到 Selinexor 的细胞毒性作用的影响，Selinexor 是一种成熟的 XPO1 抑制剂，表现为细胞活力丧失和细胞凋亡诱导。此外，我们的数据表明，与单独使用每种药物相比，Venetoclax 联合 Selinexor 可协同降低母细胞样和经典 MCL 细胞的细胞活力并增加细胞死亡。单独使用 Selinexor 或 Venetoclax 均可降低 MCL 细胞中的 MCL1 表达并增加 BAX 水平，并且这种作用通过联合方案得到进一步增强。从机制上讲，我们的研究结果表明，诱导 DNA 损伤和失活 DNA 损伤反应参与了药物联合方案的协同相互作用。总之，这项研究可能为 MCL 的治疗提供一种有吸引力的潜在治疗选择。然而，这一结论需要在体内模型中进行额外的实验验证，并且必须进行临床评估。
