The Antineoplastic Activity of Bardoxolone Methyl and a Related Triterpenoid in Leukemia Cells Is Due to Reactive Oxygen Species-Dependent Suppression of cMyc

Structurally-related pentacyclic triterpenoids methyl 2-cyano-3,12-dioxoolean-1,9dien-28-oate [Bardoxolone-methyl (Bar-Me)] and methyl 2-trifluoromethyl-3,11dioxoolean-1,12-dien-30-oate (CF3DODA-Me) contain 2-cyano-1-en-3-one and 2trifluoromethyl-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 and inhibits IKK phosphorylation and these differences may be due to steric hinderance 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 (ROS) in HL-60 and Jurkat leukemia cells, inhibit cell growth, induce apoptosis and differentiation, and decrease expression of Sp1, Sp3, Sp4 and cMyc, and these effects are significantly attenuated after cotreatment with the antioxidant glutathione (GSH). In contrast to solid tumor-derived cells, cMyc and specificity protein (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 to that observed in cells derived from solid tumors. This article has not been copyedited and formatted. The final version may differ from this version. Molecular Pharmacology Fast Forward. Published on March 8, 2017 as DOI: 10.1124/mol.116.106245 at A PE T Jornals on M arch 4, 2017 m oharm .aspeurnals.org D ow nladed from