According to recently published research from the United States, human leukemic cells are affected by a synthetic triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me)

04-17-2007

According to recently published research from the United States, human leukemic cells are affected by a synthetic triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), which 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.

"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," wrote S. Shishodia and colleagues, M.D. Anderson Cancer Center.

"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," wrote the researchers.

"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," the scientists wrote.

The authors concluded, "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."

Shishodia and colleagues published their study in Clinical Cancer Research (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. Clin Cancer Res, 2006;12(6):1828-1838).

For additional information, contact B.B. Aggarwal, University of Texas, M.D. Anderson Cancer Center, Department of Experimental Therapeutics, Cytokine Research Laboratory, 1515 Holcombe Blvd., Box 143, Houston, TX 77030, USA.

This article was prepared by Biotech Business Week editors from staff and other reports. Copyright 2007, Biotech Business Week via NewsRx.com.