The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor gamma-independent pathway.
OBJECTIVE
Ligands for the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma) are emerging as a new class of antitumor agents. Herein, we investigated the triterpenoid CDDO, a PPAR gamma ligand, for its potential as an anticancer agent on human diffuse large B-cell lymphoma (DLBCL) cells.


METHODS
The ability of CDDO to induce apoptosis in human DLBCL cells of both the germinal center and activated B-cell subtypes was determined by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay, (3)H-thymidine incorporation, and Annexin-V/propidium iodide staining. Small molecule antagonists of PPAR gamma, transfection assays, DNA binding assays, immunofluorescence, Western blotting, and NF-kappaB inhibitors were utilized to determine the contribution of PPAR gamma and NF-kappaB to the cytotoxic effects of CDDO.


RESULTS
Human DLBCL cells express PPAR gamma and PPAR gamma is activated by CDDO. In both subtypes of DLBCL cells CDDO inhibited proliferation, was cytotoxic, and induced apoptosis. The ability of CDDO to kill DLBCL cells was found to be independent of PPAR gamma activation. Interestingly, CDDO exposure resulted in activation of the p50 and p65 subunits of NF-kappaB. Moreover, the combination of CDDO with NF-kappaB inhibitors resulted in enhanced DLBCL cell death, indicating that NF-kappaB activation was a prosurvival signal.


CONCLUSIONS
These findings support the potential of CDDO, alone or in combination with NF-kappaB inhibitors, as a novel therapy for patients with DLBCL.
Ray
Denise M
DM
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Morse
Kimberly M
KM
Hilchey
Shannon P
SP
Garcia
Tatiana M
TM
Felgar
Raymond E
RE
Maggirwar
Sanjay B
SB
Phipps
Richard P
RP
Bernstein
Steven H
SH
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D047495:PPAR gamma; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D052002:NF-kappa B p50 Subunit; D047495:PPAR gamma; D051996:Transcription Factor RelA; D009828:Oleanolic Acid