PT  - JOURNAL ARTICLE
AU  - Un-Ho Jin
AU  - Yating Cheng
AU  - Beiyan Zhou
AU  - Stephen Safe
TI  - Bardoxolone Methyl and a Related Triterpenoid Downregulate cMyc Expression in Leukemia Cells
AID  - 10.1124/mol.116.106245
DP  - 2017 May 01
TA  - Molecular Pharmacology
PG  - 438--450
VI  - 91
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/91/5/438.short
4100  - http://molpharm.aspetjournals.org/content/91/5/438.full
SO  - Mol Pharmacol2017 May 01; 91
AB  - 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 IKKβ phosphorylation. 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.