Acetate Supplementation as a Means of Inducing Glioblastoma Stem-Like Cell Growth Arrest

Abstract

Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-L-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth.

Acetate as a Metabolic and Epigenetic Modifier of Cancer Therapy

“…Butyrate stimulated proliferation of normal and cancerous colonocytes when the Warburg effect is prevented, but inhibited cancerous colonocyte proliferation undergoing the Warburg effect [Donohoe et al, ]. Similarly, we showed that acetate supplementation was most effective at growth arrest of GSCs with a more glycolytic metabolism [Long et al, , ]. Collectively, these data support the use of acetate‐derived fatty acids as a therapeutic approach in a wide variety of tumor types and confirm a relationship between metabolism and epigenetics mediated by protein acetylation/deacetylation.…”

“…Physiological concentrations of sodium acetate induced apoptosis of colorectal carcinoma cells by inducing DNA fragmentation, caspase activation, lysosomal membrane permeabilization, and the appearance of a sub‐G 1 population [Marques et al, ]. Similarly, we recently demonstrated that sodium acetate induced a dose‐dependent growth arrest of glioma stem cells (GSCs) in vitro by an as yet undetermined mechanism [Long et al, , ].…”

Increasing acetyl‐CoA metabolism attenuates injury and alters spinal cord lipid content in mice subjected to experimental autoimmune encephalomyelitis

“…; Long et al . ) further supporting its role in altering cellular metabolism. More importantly, oral glyceryl triacetate increases circulating and central nervous system levels of acetate, which reduces the need for the endogenous acetate donor N ‐acetyl aspartate (Mathew et al .…”

“…Furthermore, acetate supplementation is effective in reducing tremor in a rat model for traumatic brain injury (Arun et al 2010a) and alters glioblastoma cell growth (Tsen et al 2014;Long et al 2015) further supporting its role in altering cellular metabolism. More importantly, oral glyceryl triacetate increases circulating and central nervous system levels of acetate, which reduces the need for the endogenous acetate donor N-acetyl aspartate (Mathew et al 2005).…”

Hypoxia in astrocytic tumors and implications for therapy

“…Recent studies demonstrate that human glioma stem-like cells exhibit global hypomethylation and that supplementation with Triacetin, an FDA approved food additive, reduced proliferation in a panel of 6 human primary GBM-derived glioma stem-like cell lines (Long, Tighe et al 2015). Parallel studies also show that human GBM cells grown in the brain of mice are capable of capturing and metabolizing exogenous acetate to maintain adequate pools of acetyl-CoA, with as much as 50% being derived from exogenous acetate (Mashimo, Pichumani et al 2014).…”