Overexpression of p53 delivered using recombinant NDV induces apoptosis in glioma cells by regulating the apoptotic signaling pathway

Abstract

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 and 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 and 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 . 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.

Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

“…Recombinant NDV (rNDV−p53) constructed of p53 oncolytic agent for the treatment of glioma improved the prognosis of mice with glioma due to inhibition of glioma cell growth and aggressiveness both in vitro and in vivo compared with rNDV or p53 alone. In addition, rNDV−p53 could induce apoptosis of glioma cells by upregulating apoptosis−related genes, stimulating lymphocyte infiltration and cytotoxic T lymphocyte (CTL) responses and increasing the number of apoptotic bodies in vivo (141).…”

Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas

“…In addition, P53 is also a tumor suppressor gene involved in several aspects of cell cycle control and suppression of transformation. P53-armed virus significantly decreased tumor volume and prolonged the survival of mice compared with control virus in GBM models 65,66 . A recombinant adenovirus expressing p53 in glioma cells led to biological effects of the newly expressed p53 protein, which induced apoptosis to produce rapid and generalized death of human glioma cells 67 .…”

Downregulation of TET1 Promotes Glioma Cell Proliferation and Invasion by Targeting Wnt/β-Catenin Pathway

“…To find new therapy target, great attention is paid on the investigation of molecular mechanisms for glioma progression [ 18 , 19 ]. It is proved that alteration in p53, IDH gene, and neurofibromatosis 1 gene and genes in RTK pathways and Wnt/ β -catenin pathway are appeared in glioma patients [ 20 – 23 ]. Research identifies that epigenetic alteration including aberrant DNA methylation, histone modification, and chromatin remodeling, and abnormal expression of microRNA and long-noncoding RNA played a critical role in the progression of glioma [ 24 ].…”

“…To find new therapy target, great attention is paid on the investigation of molecular mechanisms for glioma progression [18, 19]. It is proved that alteration in p53, IDH gene, and neurofibromatosis 1 gene and genes in RTK pathways and Wnt/βcatenin pathway are appeared in glioma patients [20][21][22][23].…”