Triterpenoid CDDO-Im downregulates PML/RARalpha expression in acute promyelocytic leukemia cells.
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.
Ikeda
T
T
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Kimura
F
F
Nakata
Y
Y
Sato
K
K
Ogura
K
K
Motoyoshi
K
K
Sporn
M
M
Kufe
D
D
D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D001152:Arsenicals; D007093:Imidazoles; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D009828:Oleanolic Acid; D020169:Caspases; D000077237:Arsenic Trioxide