title: Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.
abstract: Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors.
authors.affiliation: Division of Neurosurgery, Department of Surgery, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tsen
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Long
authors.forename: Heather E
authors.initials: HE
authors.lastname: Driscoll
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Davies
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Teasdale
authors.forename: Paul L
authors.initials: PL
authors.lastname: Penar
authors.forename: William W
authors.initials: WW
authors.lastname: Pendlebury
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Spees
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
authors.forename: Mariano S
authors.initials: MS
authors.lastname: Viapiano
authors.forename: Diane M
authors.initials: DM
authors.lastname: Jaworski
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002478:Cells, Cultured; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019587:Dietary Supplements; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077204:Temozolomide; D014215:Triacetin / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D001224:Aspartic Acid; D003606:Dacarbazine; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase; D014215:Triacetin; D000077204:Temozolomide
keywords: aspartoacylase; epigenetics; glioblastoma; glioma; glyceryl triacetate; metabolism; oligodendroglioma; triacetin