A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells.
The C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), a synthetic triterpenoid based on naturally occurring ursolic and oleanolic acids, induces apoptosis in tumor cells, induces differentiation, and inhibits inflammatory response through a poorly understood mechanism. Because the nuclear transcription factor nuclear factor kappaB (NF-kappaB) has been shown to suppress apoptosis and promote proliferation and is linked with inflammation and differentiation, we postulated that CDDO-Me modulates NF-kappaB activity and NF-kappaB-regulated gene expression. Using human leukemia cell lines and patient samples, we show that CDDO-Me potently inhibits both constitutive and inducible NF-kappaB activated by tumor necrosis factor (TNF), interleukin (IL)-1beta, phorbol ester, okadaic acid, hydrogen peroxide, lipopolysaccharide, and cigarette smoke. CDDO-Me was more potent than CDDO and its imidazole derivative. NF-kappaB suppression occurred through inhibition of IkappaBalpha kinase activation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and NF-kappaB-mediated reporter gene transcription. This inhibition correlated with suppression of NF-kappaB-dependent genes involved in antiapoptosis (IAP2, cFLIP, TRAF1, survivin, and bcl-2), proliferation (cyclin d1 and c-myc), and angiogenesis (VEGF, cox-2, and mmp-9). CDDO-Me also potentiated the cytotoxic effects of TNF and chemotherapeutic agents. Overall, our results suggest that CDDO-Me inhibits NF-kappaB through inhibition of IkappaBalpha kinase, leading to the suppression of expression of NF-kappaB-regulated gene products and enhancement of apoptosis induced by TNF and chemotherapeutic agents.
Cytokine Research Laboratory, Department of Experimental Therapeutics, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Shishir
S
Shishodia
Gautam
G
Sethi
Marina
M
Konopleva
Michael
M
Andreeff
Bharat B
BB
Aggarwal
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000494:pharmacology*; D020298:U937 Cells
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; D000970:Antineoplastic Agents; D007093:Imidazoles; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D053199:TNF Receptor-Associated Death Domain Protein; D014315:Triterpenes; D048069:Tumor Necrosis Factors; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D020780:Matrix Metalloproteinase 9