Department of Hematology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, 226001, PR China.
Department of Human Anatomy, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, PR China.
Arch Biochem Biophys. 2024 Nov;761:110188. doi: 10.1016/j.abb.2024.110188. Epub 2024 Oct 25.
Diffuse large B-cell lymphoma (DLBCL) is the most common malignant lymphoma in adults, and the use of rituximab has greatly improved the survival of DLBCL patients. Currently, the first-line treatment regimen for DLBCL is still rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), which significantly improves outcomes for DLBCL patients. However, a percentage of patients still experience refractory or relapsed disease. Since Dr. Brent R Stockwell proposed ferroptosis in 2012, Roudkenar, M. H. Roushandeh, A. M. Valashedi, M. R. and others proved the importance of ferroptosis in cancer drug resistance. The purpose of this study was to elucidate whether rituximab could exert anticancer effects on DLBCL cells by promoting ferroptosis. Cell viability was assessed using the Cell Counting Kit-8. The results showed that rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. Western blotting was performed to detect the levels of specific ferroptosis-associated proteins in DLBCL. Moreover, GSH depletion and MDA upregulation was assessed using GSH assays and MDA assay kits in rituximab-treated OCI-LY1 cells. In addition, rituximab failed to induce ferroptosis in rituximab-resistant cell lines. Treatment with RSL3 enhanced the effects of rituximab on DLBCL cells by inhibiting cell viability. In conclusion, we report for the first time that rituximab induces ferroptosis in lymphoma cells, at least partially through the SLC7A11/GPX4 axis. We also identify targeting ferroptosis as a promising therapeutic option for both sensitive cells and resistant cells in the treatment of DLBCL.
弥漫性大 B 细胞淋巴瘤（DLBCL）是成人中最常见的恶性淋巴瘤，利妥昔单抗的应用极大地改善了 DLBCL 患者的生存。目前，DLBCL 的一线治疗方案仍是利妥昔单抗联合环磷酰胺、多柔比星、长春新碱和泼尼松（R-CHOP），这显著改善了 DLBCL 患者的预后。然而，仍有一定比例的患者出现难治或复发。自 Brent R Stockwell 博士于 2012 年提出铁死亡以来，Roudkenar、M. H. Roushandeh、A. M. Valashedi、M. R. 等人证明了铁死亡在癌症耐药中的重要性。本研究旨在阐明利妥昔单抗是否通过促进铁死亡对 DLBCL 细胞发挥抗癌作用。采用细胞计数试剂盒-8 评估细胞活力。结果表明，利妥昔单抗暴露诱导 OCI-LY1 细胞发生铁死亡。然而，与铁死亡抑制剂 ferrostatin（Fer-1）联合使用可挽救铁死亡诱导的损伤，表明铁死亡在利妥昔单抗诱导的细胞死亡中发挥关键作用。采用 Western blot 检测 DLBCL 中特定铁死亡相关蛋白的水平。此外，采用 GSH 测定试剂盒和 MDA 测定试剂盒检测利妥昔单抗处理的 OCI-LY1 细胞中 GSH 耗竭和 MDA 上调。此外，利妥昔单抗未能诱导利妥昔单抗耐药细胞系发生铁死亡。RSL3 处理增强了利妥昔单抗对 DLBCL 细胞的作用，抑制了细胞活力。总之，我们首次报道利妥昔单抗诱导淋巴瘤细胞发生铁死亡，至少部分通过 SLC7A11/GPX4 轴。我们还确定靶向铁死亡作为治疗 DLBCL 中敏感细胞和耐药细胞的有前途的治疗选择。
