CSIG-32. MODULATION OF HALLMARKS OF GLIOBLASTOMA MULTIFORME BY BIOACTIVE PHYTOCHEMICALS: A PRECLINICAL MECHANISTIC EVALUATION

Abstract Glioblastoma multiforme (GBM) is an aggressive malignancy with extensive neovascularization, an immunosuppressive tumor microenvironment, and high recurrence rates. Bioactive plant secondary metabolites (phytochemicals), many from fruits and vegetables, have been extensively studied for GBM prevention and treatment. The objective of this study is to determine the effects of phytochemicals on GBM hallmarks and associated molecular mechanisms of action through evaluation of in vitro and in vivo studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to collect articles using PubMed, ScienceDirect and Scopus. While 1,344 articles were screened, 115 in vitro and 36 in vivo studies met our inclusion criteria. The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) review of bias tool assessed in vivo study bias. In vitro, 49 alkaloids, 10 phenolics, 2 sulfur- compounds, and 5 terpenoids modulated GBM hallmarks of cell growth, invasion, cell cycle progression, neovascularization, and apoptosis. The PI3K/Akt/mTOR pathway was suppressed by 13 phytochemicals. Apoptosis was induced by 15 phytochemicals activating caspase-3, whereas 11 compounds inhibited Bcl-2. Cell cycle modulation occurred through decreased cyclin-dependent kinases and increased p53, p21, and p27. In vivo, 17 alkaloids, 5 phenolics, 2 sulfur-compounds, and 2 terpenoids had effects on GBM hallmarks. Invasion and neovascularization were inhibited through MMP, HIF-1α, and VEGF modulation. Six phytochemicals induced apoptosis in vivo through caspases and Bcl-2. Utilizing the SYRCLE review of bias tool, the average score quality of animal studies is 10% with many indicators of bias unclear. Various phytochemicals show promise to prevent and treat GBM due to their effects on numerous GBM hallmarks. Study limitations include the inclusion of literature reporting effects of single agents and lack of clinical studies. Future research is warranted to fill gaps in our analysis before recommending phytochemicals for prevention and treatment of GBM, a perilous malignancy.