SAHA-sensitized prostate cancer cells to TNFα-related apoptosis-inducing ligand (TRAIL):: Mechanisms leading to synergistic apoptosis

Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNF alpha-Related Apoptosis-Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined with even with the lowest dose SAHA. Treatment with caspase inhibitor confirmed that SAHA-induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKK alpha, IKK beta and IKK gamma, suggesting that SAHA treatment may reduce the activity of NF kappa B. However, assay for NF kappa B luciferase reporter activity showed highly significant increase in SAHA-treated cells, supporting earlier suggestions that HDACi promotes NF kappa B transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NF kappa B activity at several regulatory steps. (c) 2006 Wiley-Liss, Inc.