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Malignant glioma is the most common primary brain carcinoma in the world and has a poor survival rate. Previous studies have demonstrated that p53 dysfunction contributes to the development and severity of malignant glioma. It has also been demonstrated that Newcastle disease virus (NDV) may be a viable candidate for the treatment of various types of cancer. In the present study, a p53 oncolytic agent delivered using recombinant NDV (rNDV-p53) was constructed and its anti-tumor effects in vitro and in vivo were assessed. Glioma cell lines and a xenograft mouse model were utilized to assess the ability of p53 and rNDV to promote apoptosis and induce immunotherapy, respectively. The mechanism of rNDV-p53 in glioma therapy was investigated using quantitative polymerase chain reaction and immunohistochemistry. Tumor-specific cytotoxic T-lymphocyte (CTL) responses and lymphocyte infiltration were also analyzed in glioma-bearing models. The results of the present study demonstrate that rNDV-p53 may be a potential therapeutic agent that improves the prognosis of mice with glioma. It was revealed that rNDV-p53 inhibits glioma cell growth and aggressiveness in vitro and in vivo compared with rNDV and p53 alone. The results also demonstrated that rNDV-p53 induced glioma cell apoptosis by upregulating apoptosis-related genes. In addition, the present study demonstrated that rNDV-p53 significantly stimulated CTL responses and lymphocyte infiltration whilst increasing the number of apoptotic bodies in vivo. Furthermore, rNDV-p53 therapy inhibited tumor regression and prolonged the survival of glioma-bearing mice. In conclusion, rNDV-p53 invoked an immune response against glioma cells, which may serve as a comprehensive immunotherapeutic schedule for glioma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]