Triterpenoid CDDO-Im downregulates PML/RARalpha expression in acute promyelocytic leukemia cells

Cell Death Differ. 2005 May;12(5):523-31. doi: 10.1038/sj.cdd.4401574.


The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of diverse human tumor cells. In the present study, we examined the effects of the CDDO imidazolide imide (CDDO-Im) on the NB4 acute promyelocytic leukemia (APL) cell line and primary APL cells. The results show that CDDO-Im selectively downregulates expression of the PML/retinoic receptor alpha fusion protein by a caspase-dependent mechanism and sensitizes APL cells to the differentiating effects of all-trans retinoic acid (ATRA). CDDO-Im treatment of APL cells was also associated with disruption of redox balance and activation of the extrinsic apoptotic pathway. In concert with these results, CDDO-Im sensitizes APL cells to arsenic trioxide (ATO)-induced apoptosis. Our findings indicate that CDDO-Im may be effective in the treatment of APL by: (i) downregulation of PML/RARalpha; (ii) enhancement of ATRA-induced differentiation; and (iii) sensitization of ATO-induced APL cell death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Down-Regulation / drug effects*
  • Gene Expression Regulation, Leukemic / drug effects*
  • Humans
  • Imidazoles / pharmacology*
  • Leukemia, Promyelocytic, Acute / metabolism*
  • Leukemia, Promyelocytic, Acute / pathology
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology
  • Oxides / pharmacology
  • Promyelocytic Leukemia Protein
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Retinoic Acid Receptor alpha
  • Transcription Factors / metabolism*
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / metabolism*


  • 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
  • Arsenicals
  • Imidazoles
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oxides
  • Promyelocytic Leukemia Protein
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Retinoic Acid Receptor alpha
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human
  • Tretinoin
  • Oleanolic Acid
  • Caspases
  • Arsenic Trioxide