title: Resveratrol targeting of AKT and p53 in glioblastoma and glioblastoma stem-like cells to suppress growth and infiltration.
abstract: OBJECTIVE Glioblastoma multiforme (GBM) is an aggressive brain cancer with median survival of less than 2 years with current treatment. Glioblastomas exhibit extensive intratumoral and interpatient heterogeneity, suggesting that successful therapies should produce broad anticancer activities. Therefore, the natural nontoxic pleiotropic agent, resveratrol, was studied for antitumorigenic 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 in mice by 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 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 antiproliferative 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; intratumoral or peritumoral resveratrol injection further suppressed growth and approximated tumor regression. Intracranial resveratrol injection resulted in 100-fold higher local drug concentration compared with intravenous delivery, and with no apparent toxicity. CONCLUSIONS Resveratrol potently inhibited GBM and GSC 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 antitumorigenic 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 the brain. Resveratrol's nontoxic nature and broad anti-GBM effects make it a compelling candidate to supplement current GBM therapies.
authors.affiliation: Departments of 1 Neurological Surgery and.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clark
authors.affiliation: Ophthalmology and Visual Sciences, and.|McPherson Eye Research Institute.
authors.forename: Saswati
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Departments of 1 Neurological Surgery and.
authors.forename: Ardem
authors.initials: A
authors.lastname: Elmayan
authors.affiliation: Ophthalmology and Visual Sciences, and.|McPherson Eye Research Institute.
authors.forename: Soesiawati R
authors.initials: SR
authors.lastname: Darjatmoko
authors.affiliation: Ophthalmology and Visual Sciences, and.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Thuro
authors.affiliation: Ophthalmology and Visual Sciences, and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yan
authors.affiliation: Ophthalmology and Visual Sciences, and.
authors.forename: Paul R
authors.initials: PR
authors.lastname: van Ginkel
authors.affiliation: Ophthalmology and Visual Sciences, and.|Carbone Cancer Center, and.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Polans
authors.affiliation: Departments of 1 Neurological Surgery and.|Carbone Cancer Center, and.|Department of Surgery, National University of Singapore.
authors.forename: John S
authors.initials: JS
authors.lastname: Kuo
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000077185:Resveratrol / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016159:Tumor Suppressor Protein p53; D000077185:Resveratrol
keywords: CED = convection-enhanced delivery; DMSO = dimethyl sulfoxide; ER = endoplasmic reticulum; GBM = glioblastoma multiforme; GSC = glioblastoma stem-like cell; PBS = phosphate-buffered saline; PCR = polymerase chain reaction; brain tumor; cancer stem-like cells; glioblastoma multiforme; natural products; oncology; resveratrol