Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells

• Published in: Molecular cancer therapeutics 2002-01, Vol.1 (3), p.177
• Main Authors: Kim, Kevin B, Lotan, Reuben, Yue, Ping, Sporn, Michael B, Suh, Nanjoo, Gribble, Gordon W, Honda, Tadashi, Wu, Gen Sheng, Hong, Waun Ki, Sun, Shi-Yong
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; bcl-2-Associated X Protein; bcl-X Protein; Blotting, Western; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - pathology; Caspase Inhibitors; Caspases - metabolism; Cell Differentiation - drug effects; Cell Division - drug effects; Cytochrome c Group - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; Mitochondria - drug effects; Mitochondria - enzymology; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - pathology
• ISSN: 1535-7163

Lung cancer continues to be the leading cause of cancer-related death in the United States. Therefore, new agents targeting prevention and treatment of lung cancer are urgently needed. In the present study, we demonstrate that a novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) is a potent inducer of apoptosis in human non-small cell lung carcinoma (NSCLC) cells. The concentrations required for a 50% decrease in cell survival (IC50) ranged from 0.1 to 0.3 microM. CDDO-Me induced rapid apoptosis and triggered a series of effects associated with apoptosis including a rapid release of cytochrome c from mitochondria, activation of procaspase-9, -7, -6, and -3, and cleavage of poly(ADP-ribose) polymerase and lamin A/C. Moreover, the caspase-3 inhibitor Z-DEVD-FMK and the pan caspase inhibitor Z-VAD-FMK suppressed CDDO-Me-induced apoptosis. These results indicate that CDDO-Me induced apoptosis in human NSCLC cells via a cytochrome c-triggered caspase activation pathway. CDDO-Me did not alter the level of Bcl-2 and Bcl-xL proteins, and no correlation was found between cell sensitivity to CDDO-Me and basal Bcl-2 expression level. Furthermore, overexpression of Bcl-2 did not protect cells from CDDO-Me-induced apoptosis. These results suggest that CDDO-Me induces apoptosis in NSCLC cells irrespective of Bcl-2 expression level. In addition, no correlation was found between cell sensitivity to CDDO-Me and p53 status, suggesting that CDDO-Me induce a p53-independent apoptosis. Our results demonstrate that CDDO-Me may be a good candidate for additional evaluation as a potential therapeutic agent for human lung cancers and possibly other types of cancer.