Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Department of Hematology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China.
Oncol Rep. 2023 Jul;50(1). doi: 10.3892/or.2023.8584. Epub 2023 Jun 16.
Despite the development of advanced therapies, the prognosis of non‑Hodgkin lymphoma (NHL) remains unsatisfactory due to refractory and relapsed cases. Artesunate (ART) and sorafenib (SOR) both exert potential antitumor activity in lymphoma. The present study aimed to investigate whether ART and SOR produce synergistic anti‑lymphoma effects, and to determine the potential underlying mechanisms. Cell viability assay, flow cytometry, malondialdehyde assay, GSH assay and western blotting were performed to evaluate cell viability, and changes in apoptosis, autophagic vacuoles, reactive oxygen species, mitochondrial membrane potential, lipid peroxidation and protein expression. The results demonstrated that ART and SOR synergistically inhibited the viability of NHL cells. ART and SOR also synergistically induced apoptosis, and markedly increased the expression levels of cleaved caspase‑3 and poly (ADP‑ribose) polymerase. Mechanistically, ART and SOR synergistically induced autophagy, and rapamycin enhanced the ART‑ or SOR‑induced inhibition of cell viability. Furthermore, it was demonstrated that ferroptosis promoted ART‑ and SOR‑induced cell death through increasing lipid peroxides. Erastin enhanced the inhibitory effects of ART and SOR on cell viability, whereas ferrostatin‑1 reduced the ART‑ and SOR‑induced apoptosis of SU‑DHL4 cells. Further studies revealed that signal transducer and activator of transcription 3 (STAT3) contributed to ferroptosis induced by ART and SOR in NHL cells, and genetic inhibition of STAT3 promoted ART/SOR‑induced ferroptosis and apoptosis, concomitantly reducing the expression levels of glutathione peroxidase 4 and myeloid cell leukemia‑1. Moreover, the combined treatment of ART and SOR exerted inhibitory effects on tumor growth, as well as antiangiogenic activity, resulting in the inhibition of CD31 expression in a xenograft model. Collectively, these findings indicated that ART acted synergistically with SOR to inhibit cell viability, and to induce apoptosis and ferroptosis through regulating the STAT3 pathway in NHL. Notably, ART and SOR may act as potential therapeutic agents for the treatment of lymphoma.
尽管已经开发出了先进的治疗方法，但由于难治性和复发性病例，非霍奇金淋巴瘤 (NHL) 的预后仍然不理想。青蒿琥酯 (ART) 和索拉非尼 (SOR) 在淋巴瘤中均具有潜在的抗肿瘤活性。本研究旨在探讨 ART 和 SOR 是否产生协同抗淋巴瘤作用，并确定潜在的机制。通过细胞活力测定、流式细胞术、丙二醛测定、GSH 测定和 Western blot 分析来评估细胞活力以及凋亡、自噬小体、活性氧、线粒体膜电位、脂质过氧化和蛋白表达的变化。结果表明，ART 和 SOR 协同抑制 NHL 细胞活力。ART 和 SOR 还协同诱导细胞凋亡，并显著增加 cleaved caspase-3 和多聚 (ADP-核糖) 聚合酶的表达水平。机制上，ART 和 SOR 协同诱导自噬，雷帕霉素增强了 ART 或 SOR 诱导的细胞活力抑制作用。此外，研究表明铁死亡通过增加脂质过氧化物促进了 ART 和 SOR 诱导的细胞死亡。恩杂鲁胺增强了 ART 和 SOR 对细胞活力的抑制作用，而 ferrostatin-1 降低了 ART 和 SOR 诱导的 SU-DHL4 细胞凋亡。进一步的研究表明，信号转导和转录激活因子 3 (STAT3) 参与了 ART 和 SOR 在 NHL 细胞中诱导的铁死亡，基因抑制 STAT3 促进了 ART/SOR 诱导的铁死亡和凋亡，同时降低了谷胱甘肽过氧化物酶 4 和髓样细胞白血病 1 的表达水平。此外，ART 和 SOR 的联合治疗对肿瘤生长和抗血管生成活性均具有抑制作用，导致异种移植模型中 CD31 表达的抑制。总之，这些发现表明，ART 与 SOR 协同作用，通过调节 STAT3 通路抑制 NHL 细胞活力，并诱导细胞凋亡和铁死亡。值得注意的是，ART 和 SOR 可能作为治疗淋巴瘤的潜在治疗药物。
