Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways.

Abstract

In the present study, we aimed to elucidate the mechanism responsible for the interactive effects of histone deacetylase (HDAC) inhibitors [suberoylanilide hydroxamic acid (SAHA), MS-275, m-carboxycinnamic acid bishydroxamide (CBHA), and trichostatin-A (TSA)] and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on apoptosis in leukemia cells. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in leukemia cells (HL60, Jurkat, K562, and U937) through multiple mechanisms; up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa and PUMA, down-regulation of IAPs, Mcl-1, Bcl-2, Bcl-XL and cFLIP, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/Htr2) to the cytosol, induction of p21WAF1/CIP1 and p27KIP1, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). The sequential treatment of cells with HDAC inhibitors followed by TRAIL was more effective in inducing apoptosis than the concurrent treatment or single agent alone. The up-regulation of death receptors and inhibition of cFLIP by HDAC inhibitors will increase the ability of TRAIL to induce apoptosis, due to enhance activation of caspase-8, cleavage of Bid, and release of mitochondrial proteins to the cytosol, and subsequent activation of caspase-9 and caspase-3. Thus, the combination of HDAC inhibitors and TRAIL can be used as a new therapeutic approach for the treatment of leukemia.

• Authors: Sharmila Shankar, Thiyam R Singh, Tamer E Fandy, Thitidaj Luetrakul, Douglas D Ross, Rakesh K Srivastava
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 16 Issue 6 Pg. 1125-38 (Dec 2005) ISSN: 1107-3756 [Print] Greece
• PMID: 16273296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Inhibitor of Apoptosis Proteins
• Membrane Glycoproteins
• Proto-Oncogene Proteins c-bcl-2
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• TNFRSF10B protein, human
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• Caspases
• Histone Deacetylases

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (pharmacology)
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Histone Deacetylase Inhibitors
• Histone Deacetylases (metabolism)
• Humans
• Inhibitor of Apoptosis Proteins
• Leukemia (metabolism, pathology)
• Membrane Glycoproteins (pharmacology)
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor (metabolism)
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha (pharmacology)