HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma.
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.
Singh
Thiyam Ramsing
TR
Department of Pharmaceutical Sciences, Molecular and Cellular Biology Program, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201-1180, USA.
Shankar
Sharmila
S
Srivastava
Rakesh K
RK
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha