Histone deacetylase inhibition and blockade of the glycolytic pathway synergistically induce glioblastoma cell death.

Abstract

High-grade gliomas are difficult to treat due to their location behind the blood-brain barrier and to inherent radioresistance and chemoresistance. 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. 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 up-regulate p21, which is blocked by concomitant administration of 2-deoxy-d-glucose. We propose simultaneous blockade of histone deacetylation and glycolysis as a novel therapeutic strategy for several major cancers.