Every year, 12,000 people in the U.S. die from renal cell carcinoma. Current therapies include partial or complete nephrectomy or treatments such as administration of IFN-α and/or interleukins that are moderately effective, at best. Moreover, the current therapies are invasive and inefficient and new therapies are needed. Histone deacetylase (HDAC) inhibitors have recently been found to sensitize cells to apoptosis-inducing agents, although the mechanism of this action is largely unknown. The current study has investigated the potential of using five different histone deacetylase inhibitors (HDACI) (depsipeptide, MS-275, oxamflatin, sodium butyrate, and trichostatin A) to sensitize TNF-related apoptosis-inducing ligand (TRAIL)/Apo-2L-resistant renal cell carcinoma cells to TRAIL/ Apo-2L-induced apoptosis. Sodium butyrate and trichostatin A each enhanced TRAIL/ Apo-2L-mediated tumor cell death to a greater extent than the other HDACI. Annexin V staining and caspase activity demonstrated the mechanism of cell death was apoptosis. Both sodium butyrate and trichostatin A treatment also increased mRNA and surface expression of TRAIL receptor 2 that was dependent on the transcription factor Sp1, thus providing a possible mechanism behind the increased sensitivity to TRAIL/Apo-2L. These results indicate that combination therapy of HDACI, such as sodium butyrate and trichostatin A, and TRAIL/Apo-2L has great potential for an efficient alternative therapy for renal cell carcinoma.
Bibliographical noteFunding Information:
ported by a Pilot & Feasibility Grant administered Cancer is probably the most common disease associated with the inhibition of apoptosis, by the O’B©rien Kidney Disease Center Program and the development of therapeutic agents targeting the apoptosis pathway within tumor Cancer Institute (CA109446-01).Project (2 P50 DK052617-06A1) and the National cells have consequently become intensely investigated. Of those areas being studied, the triggering of death receptors has high interest and therapeutic potential. Death receptors are cell surface receptors that transmit apoptotic signals through an active, instructive 2005 LADES BOSCECE process when bound by their cognate ligands. The death receptors belong to the tumor necrosis factor (TNF) receptor superfamily, characterized by similar, cysteine-rich extra-cellular domains, and contain a homologous cytoplasmic sequence called the death domain (DD) that serves as a recognition point for the apoptotic machinery.7-10The ligands for the death receptors belong to the TNF family of cytokines, a group of molecules that influence a variety of immunological functions. Two of the most studied death ligands are TNF and Fas ligand (FasL), which induce apoptosis in many physiological processes, such
- Renal cell carcinoma