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RSL3 is a type of small molecular compound which can inactivate glutathione peroxidase 4 (GPX4) and induce ferroptosis, but its role in glioma cell death remains unclear. In this study, we found RSL3 inhibited the viabilities of glioma cells and induced glioma cell death in a dose-dependent manner. In vitro studies revealed that RSL3-induced cell death was accompanied with the changes of autophagy-associated protein levels and was alleviated by pretreatment of 3-Methyladenine, bafilomycin A1 and knockdown of ATG5 with siRNA. The ATP and pyruvate content as well as the protein levels of HKII, PFKP, PKM2 were decreased in cells treated by RSL3, indicating that RSL3 induced glycolysis dysfunction in glioma cells. Moreover, supplement of exterior sodium pyruvate, which was a final product of glycolysis, not only inhibited the changes of autophagy-associated protein levels caused by RSL3, but also prevented RSL3-induced cell death. In vivo data suggested that the inhibitory effect of RSL3 on the growth of glioma cells was associated with glycolysis dysfunction and autophagy activation. Taken together, RSL3 induced autophagic cell death in glioma cells via causing glycolysis dysfunction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Programmed necrosis is established as a new form of programmed cell death and is emerging as a new strategy of treatment for cancers. Pristimerin is a natural chemical with anti-tumor effect despite the fact that its mechanism remains poorly understood. In this study, we used glioma cell lines and mice model of xenograft glioma to investigate the effect of pristimerin on glioma and its underlying mechanism. We found that pristimerin inhibited the viabilities of glioma cells in vitro and the growth of xenograft gliomas in vivo, which was accompanied by upregulation of JNK and phosphor-JNK, nuclear accumulation of AIF, and elevation in the ratio of Bax/Bcl-2. In vitro studies showed that pristimerin induced necrosis in glioma cells, as well as mitochondrial depolarization, overproduction of ROS and reduction of GSH. Ablation of AIF level with SiRNA mitigated pristimerin-induced nuclear accumulation of AIF and prevented necrosis in glioma cells. Moreover, pharmacological inhibition of JNK with SP600125 or knockdown of its level with SiRNA reversed mitochondrial depolarization attenuated the elevation of Bax/Bcl-2 and suppressed nuclear accumulation of AIF. Further, inhibition of ROS with NAC not only rescued glioma cell necrosis but also suppressed JNK activation, mitigated Bax/Bcl-2 ratio, maintained mitochondrial membrane potential, and inhibited AIF translocation into nucleus. Therefore, we demonstrated first in this study that pristimerin triggered AIF-dependent necroptosis in glioma cells via induction of mitochondrial dysfunction by activation of JNK through overproduction of ROS. These results suggest that pristimerin has potential therapeutic effects on glioma., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Parthanatos is a new form of programmed cell death that is regulated by hyper-activated PARP-1, and is emerging as a new strategy to kill cancer cells. Deoxypodophyllotoxin (DPT) is a natural chemical that is found to induce cancer cell death, in which the role of parthanatos is unknown. Thus, we investigated this issue in this study by using glioma cell lines and mice model of xenograft glioma. We found that DPT induced glioma cell death in vitro and inhibited the growth of xenograft glioma in vivo, which was accompanied with parthanatos-related biochemical events including expressional upregulation of PARP-1, cytoplasmic accumulation of PAR polymer, and nuclear translocation of AIF. In vitro study revealed that genetic knockdown of PARP-1 with small interfering RNA attenuated DPT-induced elevation in the cytoplasmic PAR-polymer and the nuclear AIF, as well as protected glioma cells against the toxicity of DPT. Further, antioxidant NAC, as well as PARP-1 inhibitor 3AB, not only alleviated the overproduction of ROS caused by DPT, but also reversed the above-mentioned biochemical events, maintained mitochondrial membrane potential and rescued glioma cells death. Therefore, we demonstrated that deoxypodophyllotoxin triggered parthanatos in glioma cells via induction of excessive ROS., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Shikonin was reported to induce necroptosis in leukemia cells, but apoptosis in glioma cell lines. Thus, it is needed to clarify whether shikonin could cause necroptosis in glioma cells and investigate its underlying mechanisms., Methods: Shikonin and rat C6 glioma cell line and Human U87 glioma cell line were used in this study. The cellular viability was assayed by MTT. Flow cytometry with annexin V-FITC and PI double staining was used to analyze cellular death modes. Morphological alterations in C6 glioma cells treated with shikoinin were evaluated by electronic transmission microscopy and fluorescence microscopy with Hoechst 33342 and PI double staining. The level of reactive oxygen species was assessed by using redox-sensitive dye DCFH-DA. The expressional level of necroptosis associated protein RIP-1 was analyzed by western blotting., Results: Shikonin induced cell death in C6 and U87 glioma cells in a dose and time dependent manner. The cell death in C6 and U87 glioma cells could be inhibited by necroptosis inhibitor necrotatin-1, not by pan-caspase inhibitor z-VAD-fmk. Shikonin treated C6 glioma cells presented electron-lucent cytoplasm, loss of plasma membrane integrity and intact nuclear membrane in morphology. The increased ROS level caused by shikonin was attenuated by necrostatin-1 and blocking ROS by anti-oxidant NAC rescued shikonin-induced cell death in both C6 and U87 glioma cells. Moreover, the expressional level of RIP-1 was up-regulated by shikonin in a dose and time dependent manner as well, but NAC suppressed RIP-1 expression., Conclusions: We demonstrated that the cell death caused by shikonin in C6 and U87 glioma cells was mainly via necroptosis. Moreover, not only RIP-1 pathway, but also oxidative stress participated in the activation of shikonin induced necroptosis.

Glioma still remains a major health problem in the world. Celastrol has been proved to be an effective natural proteasome inhibitor and was used for treatment of autoimmune disease, chronic inflammation and neurodegenerative disease. However, its effect on glioma is unclear. In this study, we investigated the therapeutic effects of celastrol on C6 glioma cells. The results demonstrated that celastrol inhibited cell proliferation in a time- and dose-dependent manner, suppressed proteasome chymotrypsin-like activity and induced apoptosis and cell cycle arrest at G2/M phase in C6 cells. Proapoptosis proteins bax and caspase-3 were up-regulated, as well as cell cycle G2/M-related proteins cyclin B(1), p21 and p27. Conversely, anti-apoptosis proteins bcl-2 and XIAP and cell cycle regulator cyclin-dependent kinase 2 were down-regulated. Taken together, our data suggest that celastrol can suppress proteasome activity and induce apoptosis and cell cycle arrest in C6 glioma cells, which make it be a potential drug for glioma.

Gliomas are malignant primary brain tumors with high morbidity. This tumor has a feature of resistance to chemotherapy and radiotherapy and the underlying mechanism is not yet clear. Autophagy is an evolutionarily conserved process of cytoplasm and cellular organelle in lysosome degradation. Under poor conditions, cells use autophagy to recycle cellular components to sustain metabolism and to prevent the accumulation of damaged, toxic proteins and organelles. More and more recent experimental results suggest that autophagy allows tumor cells survive gene therapy, chemotherapy or nutrient deficient environment. Therefore, we propose the hypothesis that autophagy may be one of the factors influencing on malignant glioma's resistance to therapy. Although there is not yet reaching an agreement about the effects of autophagy on tumor cells survival and death and much more studies are needed to prove the effects of autophagy on malignant gliomas, it gives us a new direction to investigate the mechanism underlying therapy resistance of malignant gliomas.