Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

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.

A novel membrane-associated glycovariant of BEHAB/brevican is up-regulated during rat brain development and in a rat model of invasive glioma.

BEHAB (brain-enriched hyaluronan-binding protein)/brevican is the most abundant chondroitin sulfate proteoglycan in the extracellular matrix of the adult rat brain. BEHAB/brevican expression is up-regulated coincident with glial cell proliferation and/or motility, including during early central nervous system development and in invasive glioma. An understanding of the molecular interactions that mediate BEHAB/brevican function is still in its infancy because of the existence of several BEHAB/brevican isoforms, each of which may mediate different functions. Here, we describe a novel BEHAB/brevican isoform, B/b130, and demonstrate that it is neither the glycosylphosphatidylinositol-linked splice variant of BEHAB/brevican nor a cleavage product of the full-length protein (B/b150). B/b130 is an underglycosylated isoform of BEHAB/brevican, lacking glycosaminoglycan chains as well as most of the sugars that invest B/b150. B/b130 localizes exclusively to the particulate fraction of rat brain and associates with the cell membrane by a previously undescribed calcium-independent mechanism. In addition, B/b130 is the major isoform of BEHAB/brevican that is up-regulated in a rat model of invasive glioma and may therefore contribute to the invasive ability of glioma cells. Further understanding of BEHAB/brevican isoforms will advance our knowledge of the function of this ECM component and may help identify new potential therapeutic targets for primary brain tumors.