NF-kappaB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs).
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.
Kerbauy
Daniella M B
DM
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D1-100, PO Box 19024, Seattle, WA, 98109-1024, USA.
Lesnikov
Vladimir
V
Abbasi
Nissa
N
Seal
Sudeshna
S
Scott
Bart
B
Deeg
H Joachim
HJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D000068800:Etanercept; D005434:Flow Cytometry; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D006131:Growth Inhibitors; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010087:Oxides; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione; D000068800:Etanercept; D000077237:Arsenic Trioxide