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.