HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma.

Abstract

Histone deacetylase (HDAC) inhibitors induce differentiation and/or apoptosis in a variety of cell types by activating transcription of target genes. Activation of the death receptor (DR) pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis preferentially in cancer cells. Here, we investigated the intracellular mechanisms by which HDAC inhibitors (suberoylanilide hydroxamic acid, m-carboxycinnamic acid bis-hydroxamide, MS-275 and trichostatin A) enhance the apoptosis-inducing potential of TRAIL in breast cancer cells in vitro. A synergism in apoptosis was observed in both TRAIL-sensitive and -resistant cells upon sequential treatments with HDAC inhibitors followed by TRAIL. HDAC inhibitors synergized with TRAIL by inducing DRs DR4/TRAIL-R1 and DR5/TRAIL-R2 through NFkappaB activation and some of the proapoptotic members of the Bcl-2 family, and engaging the mitochondrial pathway. The ability of HDAC inhibitors to sensitize TRAIL-resistant cells suggests that HDAC inhibitors may induce fundamental alterations in cell signaling pathways. Thus, the sequential treatments with HDAC inhibitors followed by TRAIL may be used as a new therapeutic approach for the treatment of human cancers.

• Authors: Thiyam Ramsing Singh, Sharmila Shankar, Rakesh K Srivastava
• Journal: Oncogene (Oncogene) Vol. 24 Issue 29 Pg. 4609-23 (Jul 07 2005) ISSN: 0950-9232 [Print] England
• PMID: 15897906 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Apoptosis Regulatory Proteins
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Membrane Glycoproteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha

Topics

• Apoptosis
• Apoptosis Regulatory Proteins
• Breast Neoplasms (genetics, pathology)
• Enzyme Inhibitors (pharmacology)
• Histone Deacetylase Inhibitors
• Humans
• Membrane Glycoproteins (physiology)
• Signal Transduction
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (physiology)