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.
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.
Kim
Kevin B
KB
Department of Thoracic/Head and Neck Medical Oncology, Box 432, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Lotan
Reuben
R
Yue
Ping
P
Sporn
Michael B
MB
Suh
Nanjoo
N
Gribble
Gordon W
GW
Honda
Tadashi
T
Wu
Gen Sheng
GS
Hong
Waun Ki
WK
Sun
Shi-Yong
SY
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D020169:Caspases