TY - JOUR
T1 - Bardoxolone methyl and a related triterpenoid downregulate cMyc expression in leukemia cells
AU - Jin, Un Ho
AU - Cheng, Yating
AU - Zhou, Beiyan
AU - Safe, Stephen
N1 - Funding Information:
This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P30-ES023512]; Texas AgriLife Research; and the Sid Kyle Endowment.
Publisher Copyright:
Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2017/5
Y1 - 2017/5
N2 - 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 IKKb 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.
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 IKKb 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.
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U2 - 10.1124/mol.116.106245
DO - 10.1124/mol.116.106245
M3 - Article
C2 - 28275049
AN - SCOPUS:85017327818
SN - 0026-895X
VL - 91
SP - 438
EP - 450
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -