Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells

Abstract

Abstract. Histone deacetylase inhibitors (HDIs) are a promising new class of antineoplastic agents with the ability to induce apoptosis and growth arrest of cancer cells. In addition, HDIs have been suggested to enhance the anticancer efficacy of other therapeutic regimens, such as ionizing radiation (IR) or chemotherapy. The objective of this study was to evaluate the activity of HDIs against medulloblastoma cells when applied either as single agents or in combination with IR, cytostatics, or TRAIL. The HDIs, suberoyl anilide hydroxamic acid (SAHA), sodium butyrate, and trichostatin A, were examined for their effects on the medulloblastoma cell lines, DAOY and UW228-2. We found that treatment with HDIs induced the dissipation of mitochondrial membrane potential, activation of caspase-9 and -3 and, consequently, apoptotic cell death. Moreover, all three HDIs significantly enhanced the cytotoxic effects of IR in DAOY cells. Likewise, treatment with SAHA markedly augmented the cytotoxicity of etoposide, while it had no effect on vincristine-mediated cell death. HDIs also potently increased the killing efficiency of TRAIL. TRAIL-induced, but not SAHA-induced, cell killing could be prevented by the caspase-8 inhibitor, z-IEDT-fmk. We conclude that HDIs may be useful for the treatment of medulloblastoma as monotherapy and particularly when given in combination with IR, appropriate cytostatics, or TRAIL.

Histone Deacetylase Inhibitor Sodium Butyrate Enhances the Cell Killing Effect of Psoralen plus UVA by Attenuating Nucleotide Excision Repair

“…Recently, the use of HDACI, in combination with various inducers of cell death, such as ionizing radiation and anticancer drugs, has attracted considerable attention (6)(7)(8)(9)(10)(11)(12)(13). Among these combinations, we believe the HDACI-PUVA treatment presented in this study to be one of the most effective.…”

“…3). The dose ranges of the anticancer drugs used here were based on other papers (11)(12)(13)23) and are comparable with or higher than the maximally achieved therapeutic concentrations in humans (24). In all cases, combined treatment with SB and anticancer drugs resulted in augmented cytotoxicity compared with single treatments with anticancer drugs.…”

“…Enhancement of the cell killing effects of radiation and anticancer drugs by various HDACI [sodium butyrate (SB), trichostatin A (TSA), suberoylanilide hydroxamic acid, valproic acid, etc. ], due to a marked induction of apoptosis, has been reported (6)(7)(8)(9)(10)(11)(12)(13). However, the degree of enhancement is highly dependent on the combination of HDACI and cytotoxic agent and on cell type.…”

Evaluation of the In vitro and In vivo Antitumor Activity of Histone Deacetylase Inhibitors for the Therapy of Retinoblastoma

“…The antitumor effects of demethylation inhibitors in RB cells, alone and in combination with HDACi or current regimens, should be investigated. HDACi have also been shown to synergize with tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) administration by upregulating receptor components and increasing signaling of the ligand-receptor complexes for activation of death receptor pathways (44,45,49). Poulaki et al (50) have suggested that RB cells are resistant to TRAIL -mediated apoptosis due to silencing of caspase-8 expression.…”

HDAC5 and HDAC9 in Medulloblastoma: Novel Markers for Risk Stratification and Role in Tumor Cell Growth

“…A wide body of literature provides evidence for effective treatment of different tumor cells using HDAC inhibitors (HDACi) in vitro and in vivo, such as leukemia (8), lymphoma (9), lung cancer (10,11), retinoblastoma (12), and neuroblastoma (13,14). Brain tumor cells seem to be susceptible to treatment with HDACi as has been shown for glioblastoma (15,16), atypical teratoid/rhabdoid tumor (17), and medulloblastoma (17)(18)(19). HDACis have only recently been introduced in the clinical setting of cancer treatment, with Vorinostat being the first HDACi approved for the treatment of cutaneous T-cell lymphoma by the Food and Drug Administration (20).…”