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Mol Pharmacol. 2017 May;91(5):438-450. doi: 10.1124/mol.116.106245. Epub 2017 Mar 8.

Bardoxolone Methyl and a Related Triterpenoid Downregulate cMyc Expression in Leukemia Cells.

Author information

1
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
2
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas ssafe@cvm.tamu.edu.

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 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.

PMID:
28275049
PMCID:
PMC5399643
DOI:
10.1124/mol.116.106245
[Indexed for MEDLINE]
Free PMC Article

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