Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels.
The synthetic triterpenoid CDDO-Im-induced apoptosis of patient-derived AML blasts: 11/25 AMLs were highly sensitive, while the remaining were moderately sensitive to CDDO-Im. The addition of TRAIL significantly potentiated the cytotoxic effect of CDDO-Im, through mechanisms involving the induction of TRAIL-R1/TRAIL-R2 and downmodulation of TRAIL-R3/TRAIL-R4. Biochemical studies showed that CDDO-Im: induced a rapid and marked GSH depletion and antioxidants (GSH or NAC) completely inhibited its pro-apoptotic effect; sequentially activated caspase-8, -9 and -3; caspase inhibitors partially protected AML blasts from CDDO-Im-induced apoptosis; resistance of AML blasts to CDDO-Im-induced apoptosis correlated with low caspase-8/FADD and high Bcl-X(L) expression in leukemic blasts.
Riccioni
Roberta
R
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Senese
Mara
M
Diverio
Daniela
D
Riti
Viviana
V
Mariani
Gualtiero
G
Boe
Alessandra
A
LoCoco
Francesco
F
Foà
Robin
R
Peschle
Cesare
C
Sporn
Michael
M
Testa
Ugo
U
D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D053200:Fas-Associated Death Domain Protein; D007093:Imidazoles; D053221:TNF-Related Apoptosis-Inducing Ligand; D009828:Oleanolic Acid; D053181:Caspase 8