title: Bardoxolone Methyl and a Related Triterpenoid Downregulate cMyc Expression in Leukemia Cells.
abstract: Structurally related pentacyclic triterpenoids methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate [bardoxolone-methyl (Bar-Me)] and methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF3DODA-Me) contain 2-cyano-1-en-3-one and 2-trifluoromethyl-1-en-3-one moieties, respectively, in their A-rings and differ in the position of their en-one structures in ring C. Only Bar-Me forms a Michael addition adduct with glutathione (GSH) and inhibits IKKβphosphorylation. These differences may be due to steric hindrance by the 11-keto group in CF3DODA-Me, which prevents Michael addition by the conjugated en-one in the A-ring. In contrast, both Bar-Me and CF3DODA-Me induce reactive oxygen species in HL-60 and Jurkat leukemia cells, inhibit cell growth, induce apoptosis and differentiation, and decrease expression of specificity proteins (Sp) 1, 3, and 4, and cMyc, and these effects are significantly attenuated after cotreatment with the antioxidant GSH. In contrast to solid tumor-derived cells, cMyc and Sp transcriptions are regulated independently and cMyc plays a more predominant role than Sp transcription factors in regulating HL-60 or Jurkat cell proliferation and differentiation compared with that observed in cells derived from solid tumors.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Un-Ho
authors.initials: UH
authors.lastname: Jin
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Yating
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D007938:Leukemia / Q000473:pathology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051703:Sp Transcription Factors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D051703:Sp Transcription Factors; D014315:Triterpenes; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase; D005978:Glutathione