Histone Deacetylase Inhibition and Blockade of the Glycolytic Pathway Synergistically Induce Glioblastoma Cell Death

Abstract

Purpose: High-grade gliomas are difficult to treat due to their location behind the blood-brain barrier and to inherent radioresistance and chemoresistance. Experimental Design: Because tumorigenesis is considered a multistep process of accumulating mutations affecting distinct signaling pathways, combinations of compounds, which inhibit nonoverlapping pathways, are being explored to improve treatment of gliomas. Histone deacetylase inhibitors (HDI) have proven antitumor activity by blocking cell proliferation, promoting differentiation, and inducing tumor cell apoptosis. Results: In this report, we show that the HDIs trichostatin A, sodium butyrate, and low nanomolar doses of LAQ824 combined with the glycolysis inhibitor 2-deoxy-D-glucose induce strong apoptosis in cancer cell lines of brain, breast, and cervix in a p53-independent manner. HDIs upregulate p21, which is blocked by concomitant administration of 2-deoxy-D-glucose. Conclusions: We propose simultaneous blockade of histone deacetylation and glycolysis as a novel therapeutic strategy for several major cancers.Glioblastoma multiforme (GBM) are the most frequent human brain tumors. These aggressive, highly invasive, and neurologically destructive tumors are among the deadliest of human cancers, with a median survival ranging from 9 to 12 months (1). Despite treatment efforts including new technological advances in neurosurgery, radiation therapy, and clinical trials with novel therapeutic agents (2), median survival has not changed significantly over the past two decades. Meanwhile, cancer drug development has been moving from conventional cytotoxic chemotherapeutics to more sophisticated drugs exploiting biological mechanism of tumorigenesis (3).In high-grade gliomas, several genes and pathways are altered due to a severe mutator phenotype that leads to the accumulation of mutations in critical regulatory genes. Mutations of PTEN, RB, p16/p14, p53 (4), and receptor tyrosine kinase (5 -7) result in up-regulation of pathways that promote tumor growth, invasion, and resistance to apoptotic stimuli (8).Besides classic mutations, epigenetic silencing of tumor suppressor genes frequently leads to dysregulation of signaling pathways promoting tumorigenesis. Histone acetyltransferase and histone deacetylase (HDAC) catalyze the acetylation and deacetylation of lysine residues in the tails of histone proteins (e.g., lysine residue in histones 3 and 4), regulating the affinity of the protein transcriptional complexes to the DNA (9). Thus, the recruitment of histone acetyltransferase and HDAC is considered as a key element in the dynamic regulation of genes involved in cellular proliferation and differentiation during normal development and carcinogenesis (10). HDAC inhibitors (HDI) induce re-expression of silenced tumor suppressor genes (11,12). HDIs induce differentiation and promote apoptosis in transformed and cancerous but not in normal cells (11,13). HDIs have been classified in different classes: shortchain fatty acid (as sodium butirrate, valproic...

2-Deoxy d-Glucose Prevents Cell Surface Expression of NKG2D Ligands through Inhibition of N-Linked Glycosylation

“…2DG is currently in clinical trials for use as a chemotherapeutic agent. Several studies have furthermore shown a synergistic effect of 2DG in combination with other cancer therapeutics, including HDAC inhibitors (43,44). Therapeutic synergy has been shown between a novel HDAC inhibitor LAQ824 (that can pass the blood-brain barrier) and 2DG in treatment of glioblastoma (44).…”

“…Several studies have furthermore shown a synergistic effect of 2DG in combination with other cancer therapeutics, including HDAC inhibitors (43,44). Therapeutic synergy has been shown between a novel HDAC inhibitor LAQ824 (that can pass the blood-brain barrier) and 2DG in treatment of glioblastoma (44). We would predict that this regimen will limit the NKG2D ligand surface expression on glioblastoma cells; however, the potential implication of this needs to be established.…”

BUTYRATE SUPPLEMENTATION AFFECTS mRNA ABUNDANCE OF GENES INVOLVED IN GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION AND LIPOGENESIS IN THE RUMEN EPITHELIUM OF HOLSTEIN DAIRY COWS

“…In glioma cells, HDAC inhibition by butyrate enhances apoptosis, but only when glycolysis is also blocked (Egler et al, 2008). Glycolysis, therefore, appears to be a crucial compensatory mechanism for HDAC inhibition.…”

Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis

“…2-DG competes with glucose as a substrate for hexokinase preventing glucose phosphorylation and oxidation via glycolysis. In animal models, 2-DG selectively induced cell death in transformed cells when used in combination with other anticancer therapeutics such as paclitaxel or histone deacetylase (HDAC) inhibitors (Maschek et al 2004, Egler et al 2008. Similarly, the hexokinase inhibitor 3-Br suppressed xenograft growth of human colorectal carcinoma cells containing activated alleles of Ras or Raf, though it was not clear whether this activity is due to cytotoxic versus cytostatic effects (Yun et al 2009).…”