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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.

SUBMITTER: Tsen AR

PROVIDER: S-EPMC3947395 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Tsen Andrew R AR Long Patrick M PM Driscoll Heather E HE Davies Matthew T MT Teasdale Benjamin A BA Penar Paul L PL Pendlebury William W WW Spees Jeffrey L JL Lawler Sean E SE Viapiano Mariano S MS Jaworski Diane M DM

International journal of cancer 20130930 6

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 triaceta ...[more]

PMID: 23996800

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Project description:BACKGROUND:SOX2 is regarded as an important marker in stem cell. The change of SOX2 expression after adjuvant therapy in high grade glioma (HGG) remains unknown so far. Few patients with recurrent glioma have opportunity to undergo operation once again, so the recurrent glioma samples are scarce. This study tries to analyze SOX2 expression in paired primary and recurrent HGG, aims to better understand the transformation law of SOX2 after adjuvant therapy in HGG. METHODS:Twenty-four recurrent HGG patients who undergone a second resection were included. 16 patients received adjuvant therapy, the remaining 8 patients didn't receive any adjuvant therapy at all. The protein expression of SOX2 in paired primary and recurrent HGG was tested by immunohistochemistry. The statistical analysis was conducted by IBM SPSS Statistics 19.0. RESULTS:In primary HGG, SOX2 expression of 3?+?, 2?+?, 1+ and 0+ were seen in 20 (83.3%), 1 (4.2%), 1 (4.2%) and 2 cases (8.3%), respectively. The expression of SOX2 was decreased in recurrent HGG compared to the paired primary sample (p?=?0.001). The decrease of SOX2 was often seen in patients received chemotherapy, radiotherapy or both (p?=?0.003). Patients with SOX2 high expression in primary glioma had a longer median PFS than those with SOX2 low expression with marginal statistic significance (12.7 vs. 5.4?months, p?=?0.083). For cases with SOX2 high expression in the primary glioma, those had SOX2 low expression after recurrence seemed to have worse prognosis as compared to patients with stable SOX2 high expression (PFS: 10.4 vs. 14.9?months, p?=?0.036; OS: 27.0 vs 49.5?months, p?=?0.005). CONCLUSIONS:This is the first study comparing the protein expression of SOX2 in recurrent HGG and its paired primary tumor. SOX2 high expression is common in brain HGG, a tendency of decreased SOX2 expression in recurrent gliomas was evidenced. Lower SOX2 expression was seen in those patients who received adjuvant chemotherapy and/or radiotherapy. Patients with low SOX2 expression in primary HGG usually have poorer prognosis, those with SOX2 expression decreased in recurrent HGG had worse outcome.

Project description:PurposeThe role of surgical resection in the treatment of brainstem glioma (BSG) is poorly understood. For pediatric low-grade (LGBSG) group, several monocentric small-scale retrospective studies reported contradictory conclusions. And there was no clinical study focused on surgical resection for adult or pediatric high-grade (HG) patient groups. This study aims to illustrate whether surgical resection and adjuvant therapy provide survival benefits for patients with histologically confirmed BSG.Patients and methodsThis retrospective cohort study included 529 patients with histologically confirmed BSG in Surveillance Epidemiology and End Results (SEER) database from 2006-2015. Patients were divided into four groups by age and World Health Organization (WHO) grade. Kaplan-Meier curves of CSS were plotted by different treatment options to compare the survival probability. Univariate and multivariable analyses were then conducted to determine the prognosis effects of surgical resection and adjuvant therapy on cancer specific survival (CSS). All analyses were done in four different groups separately.ResultsThe final sample included 529 patients. The entire study population was divided into groups of pediatric LG (n=236, 44.6%), pediatric HG (n=37, 7.0%), adult LG (n=204, 38.6%) and adult HG (n=52, 9.8%). 52.7% (n=144) of pediatric patients had pilocytic astrocytoma and 45.3% (n=116) of adult patients had ependymoma. Pediatric LGBSG group had the highest gross total resection (GTR) rate (61.4%) and 5-year CSS rate (88.6%). Kaplan-Meier curves of pediatric LGBSG group revealed that patients treated with GTR had significantly better survival probability (P=0.033). Multivariable analysis identified GTR as independently significant predictor for prolonged CSS in pediatric LGBSG group (HR0.29, 95%CI 0.11-0.78, P=0.015); Surgical resection showed no relation to CSS in other patient groups. Kaplan-Meier curves of adult HGBSG group showed that patients treated with both RT and CT in adult HGBSG group had the best survival probability (P=0.02). However, multivariable analysis showed the combination of radiotherapy (RT) and chemotherapy (CT) was not significantly related to better CSS in adult HGBSG group (HR0.35, 95%CI 0.11-1.09, P=0.070). Adjuvant therapy didn't associate with better CSS in other patient groups.ConclusionPediatric LGBSG group had the highest GTR rate and the most favorable clinical outcome. GTR can provide significant survival benefits for pediatric LGBSG group.

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Dataset Information

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

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

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