NF-kappaB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs).

Abstract

Tumor necrosis factor (TNF)-alpha, a potent stimulus of nuclear factor-kappaB (NF-kappaB), is up-regulated in myelodysplastic syndrome (MDS). Here, we show that bone marrow mononuclear cells (BMMCs) and purified CD34+ cells from patients with low-grade/early-stage MDS (refractory anemia/refractory anemia with ring sideroblasts [RA/RARS]) have low levels of NF-kappaB activity in nuclear extracts comparable with normal marrow, while patients with RA with excess blasts (RAEB) show significantly increased levels of activity (P = .008). Exogenous TNF-alpha enhanced NF-kappaB nuclear translocation in MDS BMMCs above baseline levels. Treatment with arsenic trioxide (ATO; 2-200 microM) inhibited NF-kappaB activity in normal marrow, primary MDS, and ML1 cells, even in the presence of exogenous TNF-alpha (20 ng/mL), and down-regulated NF-kappaB-dependent antiapoptotic proteins, B-cell leukemia XL (Bcl-XL), Bcl-2, X-linked inhibitor of apoptosis (XIAP), and Fas-associated death domain (FADD)-like interleukin-1beta-converting enzyme (FLICE) inhibitory protein (FLIP), leading to apoptosis. However, overexpression of FLIP resulted in increased NF-kappaB activity and rendered ML1 cells resistant to ATO-induced apoptosis. These data are consistent with the observed up-regulation of FLIP and resistance to apoptosis with advanced MDS, where ATO as a single agent may show only limited efficacy. However, the data also suggest that combinations of ATO with agents that interfere with other pathways, such as FLIP autoamplification via NF-kappaB, may have considerable therapeutic activity.

• Authors: Daniella M B Kerbauy, Vladimir Lesnikov, Nissa Abbasi, Sudeshna Seal, Bart Scott, H Joachim Deeg
• Journal: Blood (Blood) Vol. 106 Issue 12 Pg. 3917-25 (Dec 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 16105982 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Apoptosis Regulatory Proteins
• Arsenicals
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Growth Inhibitors
• Immunoglobulin G
• Intracellular Signaling Peptides and Proteins
• Membrane Glycoproteins
• NF-kappa B
• Oxides
• Receptors, Tumor Necrosis Factor
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• Glutathione
• Etanercept
• Arsenic Trioxide

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (physiology)
• Apoptosis Regulatory Proteins (metabolism)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Blotting, Western
• Bone Marrow Cells (drug effects, metabolism)
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Electrophoretic Mobility Shift Assay
• Enzyme Activation (drug effects)
• Etanercept
• Flow Cytometry
• Glutathione (drug effects, metabolism)
• Growth Inhibitors (pharmacology)
• Humans
• Immunoglobulin G (pharmacology)
• Intracellular Signaling Peptides and Proteins (drug effects, metabolism)
• Membrane Glycoproteins (metabolism)
• Myelodysplastic Syndromes (drug therapy, metabolism, pathology)
• NF-kappa B (drug effects, metabolism)
• Oxides (pharmacology)
• Protein Transport (drug effects)
• Receptors, Tumor Necrosis Factor
• Reverse Transcriptase Polymerase Chain Reaction
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha (metabolism)