Synthetic triterpenoids inhibit growth, induce apoptosis and suppress pro-survival Akt, mTOR and NF-{kappa}B signaling proteins in colorectal cancer cells.
Lack of apoptotic cell death has been implicated in malignant transformation and resistance to anticancer therapies. The promotion of apoptosis in cancer cells could potentially lead to the regression and improved prognosis of refractory colorectal cancer. Synthetic triterpenoids have shown strong antitumorigenic activity towards diverse cancer cell types, but have not been investigated for colorectal cancer. In the present study, we tested the apoptosis-inducing activity of oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) derivatives in colorectal cancer cells lines. Cell growth/viability assay (MTS) demonstrated that colorectal cancer cells are highly sensitive to CDDO-Me at concentrations of 1.25 to 10 microM. The primary mode of tumor cell destruction was apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization. Induction of apoptosis by CDDO-Me was associated with the inhibition of pro-survival Akt, NF-kappaB and mTOR signaling proteins and NF-kappaB-regulated anti-apoptotic Bcl-2, Bcl-xL, Bad and survivin. These studies provide rationale for clinical evaluation of CDDO-Me for the treatment of advanced chemotherapy refractory colorectal cancer.
Gao
Xiaohua
X
Surgical Research 4D, One Ford Place, Detroit, MI 48202, USA.
Deeb
Dorrah
D
Hao
Jiang
J
Liu
Yongbo
Y
Arbab
Ali S
AS
Dulchavsky
Scott A
SA
Gautam
Subhash C
SC
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes / Q000494:pharmacology*; D051025:bcl-Associated Death Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; C494819:BAD protein, human; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D014315:Triterpenes; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D009828:Oleanolic Acid; C445068:bardoxolone methyl; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020169:Caspases
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