The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice.
We report the first use of new synthetic triterpenoids to prevent lung cancer in experimental animals. Female A/J mice were treated with the mutagenic carcinogen vinyl carbamate, which induces adenocarcinoma of the lung in all animals within 16 weeks. If mice were fed either the methyl ester or the ethyl amide derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-ME and CDDO-EA, respectively), beginning 1 week after dosing with carcinogen, the number, size, and severity of lung carcinomas were markedly reduced. The mechanisms of action of CDDO-ME and CDDO-EA that are germane to these in vivo findings are the following results shown here in cell culture: (a) suppression of the ability of IFN-gamma to induce de novo formation of nitric oxide synthase in a macrophage-like cell line RAW264.7, (b) induction of heme oxygenase-1 in these RAW cells, and (c) suppression of phosphorylation of the transcription factor signal transducers and activators of transcription 3 as well as induction of apoptosis in human lung cancer cell lines.
Liby
Karen
K
Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755, USA.
Royce
Darlene B
DB
Williams
Charlotte R
CR
Risingsong
Renee
R
Yore
Mark M
MM
Honda
Tadashi
T
Gribble
Gordon W
GW
Dmitrovsky
Ethan
E
Sporn
Thomas A
TA
Sporn
Michael B
MB
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014520:Urethane / Q000031:analogs & derivatives
C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D016588:Anticarcinogenic Agents; D050796:STAT3 Transcription Factor; D014520:Urethane; D009828:Oleanolic Acid; C017963:vinyl carbamate; C445068:bardoxolone methyl