title: Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels.
abstract: 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.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Riccioni
authors.forename: Mara
authors.initials: M
authors.lastname: Senese
authors.forename: Daniela
authors.initials: D
authors.lastname: Diverio
authors.forename: Viviana
authors.initials: V
authors.lastname: Riti
authors.forename: Gualtiero
authors.initials: G
authors.lastname: Mariani
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boe
authors.forename: Francesco
authors.initials: F
authors.lastname: LoCoco
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Cesare
authors.initials: C
authors.lastname: Peschle
authors.forename: Michael
authors.initials: M
authors.lastname: Sporn
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
mesh_terms: 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
chemical_list: 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