Osthole induces necroptosis via ROS overproduction in glioma cells

Abstract

Glioma is a common primary malignant tumor that has a poor prognosis and often develops drug resistance. The coumarin derivative osthole has previously been reported to induce cancer cell apoptosis. Recently, we found that it could also trigger glioma cell necroptosis, a type of cell death that is usually accompanied with reactive oxygen species (ROS) production. However, the relationship between ROS production and necroptosis induced by osthole has not been fully elucidated. In this study, we found that osthole could induce necroptosis of glioma cell lines U87 and C6; such cell death was distinct from apoptosis induced by MG-132. Expression of necroptosis inhibitor caspase-8 was decreased, and levels of necroptosis proteins receptor-interacting protein 1 (RIP1), RIP3 and mixed lineage kinase domain-like protein were increased in U87 and C6 cells after treatment with osthole, whereas levels of apoptosis-related proteins caspase-3, caspase-7, and caspase-9 were not increased. Lactate dehydrogenase release and flow cytometry assays confirmed that cell death induced by osthole was primarily necrosis. In addition, necroptosis induced by osthole was accompanied by excessive production of ROS, as observed for other necroptosis-inducing reagents. Pretreatment with the RIP1 inhibitor necrostatin-1 attenuated both osthole-induced necroptosis and the production of ROS in U87 cells. Furthermore, the ROS inhibitor N-acetylcysteine decreased osthole-induced necroptosis and growth inhibition. Overall, these findings suggest that osthole induces necroptosis of glioma cells via ROS production and thus may have potential for development into a therapeutic drug for glioma therapy. Glioma is the most common central nervous system tumor in adults and children [1,2], and glioblastoma is the most malignant glioma ranked grade Ⅳ [3]. The average incidence of glioblastoma is 3.2/100 000 population, and the 5-year survival rate is about 6.8% [4]. Although the occurrence of glioblastoma is relatively Abbreviations DCFH-DA, 2 0 , 7 0-dichloro-hydrofluorescein diacetate;

Osthole: an overview of its sources, biological activities, and modification development

“…Recent research regarding the cytotoxic and antitumor activity of osthole has involved various kinds of tumor cells/models as showed in Table 2. These include breast cancer cells [26][27][28][29], ovarian carcinoma (OC) cells [30][31][32], endometrial carcinoma (EC) cells [33], head and neck squamous cell carcinoma (HNSCC) cells [34], hepatocellular carcinoma (HCC) cells [35][36][37], human gastric cancer cells [38,39], cervical cancer cells [40][41][42], rhabdomyosarcoma (RMS) cells [43], intrahepatic cholangiocarcinoma (ICC) cells [44], esophageal squamous cell carcinoma (ESCC) cells [45], renal cell carcinoma (RCC) cells [46,47], nasopharyngeal cancer (NPC) cells [48], bladder cancer cells [49], lung cancer cells [50][51][52], leukemia cells [53,54], osteosarcoma (OS) cells [55], human melanoma cells [56], and glioma cells [57].…”

“…Osthole combined with CDDP was capable of causing the apoptosis of human lung cancer cell NCI-H460 by inducing production of reactive oxygen species (ROS) [52]. Osthole has been shown to trigger glioma cell necroptosis via ROS overproduction in glioma cells U87 and C6 [57]. The antitumor activities of osthole have been investigated in vivo.…”

Osthole Induces Apoptosis and Caspase-3/GSDME-Dependent Pyroptosis via NQO1-Mediated ROS Generation in HeLa Cells

“…ROS overproduction occurs in many forms of regulated cell death, including apoptosis, necroptosis, ferroptosis, and pyroptosis [ 35 ]. It has been reported that osthole-induced antitumor effects are relevant to ROS overproduction [ 36 ], and our earlier report also proved that osthole induced ROS overproduction in glioma cells [ 37 ]. Previous reports showed that apoptosis and pyroptosis share part of the upstream signal pathway, including ROS and caspase-3 [ 22 ].…”

Natural products in suppressing glioma progression: A focus on the role of microRNAs

“…In glioblastoma, it could inhibit MMP‐13 expression and suppress migratory abilities of GBM cells (Tsai et al, 2014). Furthermore, it induces a specific type of cell death called necroptosis by overproducing ROS in U87 and C6 glioma cell lines (Huangfu et al, 2021). Lin, Gao, Shang, Sui, and Fu (2015) showed that osthole could inhibit cell proliferation and induce apoptosis by increasing caspase‐3 activity in U87 glioma cell lines in a dose‐dependent manner.…”