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.
Shishodia
Shishir
S
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.
Sethi
Gautam
G
Konopleva
Marina
M
Andreeff
Michael
M
Aggarwal
Bharat B
BB
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