Artesunate synergistically promotes sorafenib‑induced apoptosis and ferroptosis in non‑Hodgkin lymphoma cells through inhibition of the STAT3 pathway.

Abstract

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 transcription3 (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 peroxidase4 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.