A synthetic triterpenoid, CDDO-Me, inhibits I kappa B alpha, kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappa B-regulated gene products in human leukemic cells

作者：Shishodia S; Sethi G; Konopleva M; Andreeff M; Aggarwal BB^*

来源：Clinical Cancer Research, 2006, 12(6): 1828-1838.

DOI：10.1158/1078-0432.CCR-05-2044

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 kappa B (NF-kappa B) has been shown to suppress apoptosis and promote proliferation and is linked with inflammation and differentiation, we postulated that CDDO-Me modulates NF-kappa B activity and NF-kappa B-regulated gene expression. Using human leukemia cell lines and patient samples, we show that CDDO-Me potently inhibits both constitutive and inducible NF-kappa B activated by tumor necrosis factor (TNF), interleukin (IL)-1 beta phorbol ester, okadaic acid, hydrogen peroxide, lipopolysaccharide, and cigarette smoke. CDDO-Me was more potent than CDDO and its imidazole derivative. NF-kappa B suppression occurred through inhibition of I kappa B alpha kinase activation, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and NF-kappa B-mediated reporter gene transcription. This inhibition correlated with suppression of NF-kappa B-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-kappa B through inhibition Of I kappa B alpha kinase, leading to the suppression of expression of NF-kappa B-regulated gene products and enhancement of apoptosis induced by TNF and chemotherapeutic agents.

• 出版日期2006-3-15