Resveratrol targeting of AKT and p53 in glioblastoma and glioblastoma stem-like cells to suppress growth and infiltration

Abstract

Object Glioblastoma multiforme (GBM) is an aggressive brain cancer with median survival of less than two years with current treatment. GBM exhibits extensive intra-tumor and inter-patient heterogeneity, suggesting that successful therapies should exert broad anti-cancer activities. Therefore, the natural non-toxic pleiotropic agent, resveratrol, was studied for anti-tumorigenic effects against GBM. Methods Resveratrol’s effects on cell proliferation, sphere-forming ability, and invasion were tested using multiple patient-derived GBM stem-like cell (GSC) lines and established U87 glioma cells, and changes in oncogenic AKT and tumor suppressive p53 were analyzed. Resveratrol was also tested in vivo against U87 glioma flank xenografts using multiple delivery methods, including direct tumor injection. Finally, resveratrol was delivered directly to brain tissue to determine toxicity and achievable drug concentrations in the brain parenchyma. Results Resveratrol significantly inhibited proliferation in U87 glioma and multiple patient-derived GSC lines, demonstrating similar inhibitory concentrations across these phenotypically heterogeneous lines. Resveratrol also inhibited the sphere-forming ability of GSCs, suggesting anti-stem cell effects. Additionally, resveratrol blocked U87 glioma and GSC invasion in an in vitro Matrigel transwell assay at doses similar to those mediating anti-proliferative effects. In U87 glioma cells and GSCs, resveratrol reduced AKT phosphorylation and induced p53 expression and activation that led to transcription of downstream p53 target genes. Resveratrol administration via oral gavage or ad libitum in the water supply significantly suppressed GBM xenograft growth; intra-tumor or peri-tumor resveratrol injection further suppressed growth and approximating tumor regression. Intracranial resveratrol injection resulted in 100-fold higher local drug concentration compared to intravenous delivery, and with no apparent toxicity. Conclusions Resveratrol potently inhibited GBM and GBM stem-like cell growth and infiltration, acting partially via AKT deactivation and p53 induction, and suppressed glioblastoma growth in vivo. The ability of resveratrol to modulate AKT and p53, as well as reportedly many other anti-tumorigenic pathways, is attractive for therapy against a genetically heterogeneous tumor such as GBM. Although resveratrol exhibits low bioavailability when administered orally or intravenously, novel delivery methods such as direct injection (i.e. convection enhanced delivery) could potentially be used to achieve and maintain therapeutic doses in brain. Resveratrol’s non-toxic nature and broad anti-GBM effects make it a compelling candidate to supplement current GBM therapies.

miR-92a-3p Exerts Various Effects in Glioma and Glioma Stem-Like Cells Specifically Targeting CDH1/β-Catenin and Notch-1/Akt Signaling Pathways

“…Among these genes, CDH1 and Notch-1 (Figure 4A) are regarded as the regulators of Wnt/β-catenin and PI3K/Akt signaling pathways, respectively [21,22]. As the two pathways are always activated in glioma cells and GSCs [23,24,25,26], we hypothesize that CDH1 and Nocth-1 could be the direct targets of miR-92a. To test our hypothesis, qRT-PCR and Western blotting assay were applied to measure the relative expression levels of CDH1 and Notch-1 in two cell types.…”

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

“…Such an aggregation causes the nanoparticles to behave like larger particles [58] and may affect systemic delivery for therapeutic application in the brain. However, evaluation of potential therapeutics through direct intratumoral injection including nanoparticle delivery to in vivo models of GBM [59, 60] or at the point of patient tumor resection or biopsy [61–65] in several studies indicates that such systemic transport challenges can be circumvented to facilitate therapeutic delivery in a clinical setting.…”

The Therapeutic Potential of Resveratrol in Gliomas

“…Studies have proven that RSV crosses the blood brain barrier (BBB) but the specific intracranial levels have not been proven. After crossing the BBB RSV displays pleiotropic molecular consequences resulting in the modifications of several diverse signaling pathways like NF-κB, Rb-E2F, p53, phosphatidylinositol 3-kinase (PI3K)/Akt, and MAPK pathways that are imperative for GBM proliferation ( Figure 1) (1,22).…”