Triterpenoids and the rexinoid LG100268 prevent lung tumors induced by vinyl carbamate in strain A/J mice.

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Lung cancer is the leading cause of cancer deaths in the United States, and prevention is required to reduce the significant mortality and poor prognosis of this disease. Because of the emerging link between inflammation and carcinogenesis, the triterpenoids were originally developed as anti-inflammatory agents, and CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its methyl ester (CDDO-ME) are currently in Phase I clinical trial for treatment of leukemia and solid tumors. We have shown that the rexinoid LG100268 (268) has anti-inflammatory properties and is effective for the prevention of estrogen receptor-positive and -negative breast cancer in rodent models of mammary tumorigenesis. CDDO-ME and the methyl amide (CDDO-MA) and ethyl amide (CDDO-EA) of CDDO potently (IC₅₀ = 1-2 nM) inhibit nitric oxide production in RAW264.7 macrophage-like cells stimulated with IFN-gamma and LPS. Low nanomolar concentrations of these triterpenoids also block the expression of inducible nitric oxide synthase and cyclooxygenase and induce the phase 2 cytoprotective enzymes NAD(P)H quinone oxidoreductase and heme oxygenase-1. The compounds also reduce constitutive pSTAT3 levels, inhibit proliferation, and induce apoptosis in human lung cancer cells. Thus, the triterpenoids and rexinoids are promising agents for lung cancer prevention and were tested for their ability to prevent lung tumors. Female A/J mice were injected i.p. with vinyl carbamate (16 mg/kg), once a week for two weeks. One week later, the mice were fed 268 (60 mg/kg diet) or CDDO-MA (800 mg/kg diet) for 20 weeks. CDDO-MA and 268 significantly (P < 0.05) reduced the average number of tumors in the lungs from 15.5 in the control group (n = 23) to 9.1 in the CDDO-MA group (n = 16) and to 7.4 in the 268 group (n = 12). Moreover, the tumors were markedly smaller in the groups fed chemopreventive diets; 43% of tumors in the CDDO-MA group and 28% of tumors in the 268 group were less than 0.5 mm in diameter compared to only 4% in the control group. Similarly, 29% of tumors in the control group were larger than 1 mm in diameter, compared to only 1% for mice fed CDDO-MA and 7% for mice fed 268. In a second independent study, A/J mice were injected as described and were fed CDDO-ME (60 mg/kg diet) or CDDO-EA (400 mg/kg diet). After 15 weeks on diet, the average number of tumors in the control group (n = 29) was 15.9 but was only 7.4 in the CDDO-ME group and 7.8 in the CDDO-EA group (n = 12 for both groups). No tumors in either the CDDO-ME or CDDO-EA groups were larger than 1 mm in diameter, while 20% of the tumors in the control group were > 1 mm. Instead, 63% and 70% of the tumors in the CDDO-ME and CDDO-EA groups, respectively, were < 0.5 mm in diameter vs. 3% in the controls. These studies suggest that the triterpenoids and 268 were highly effective for lung cancer prevention in a mouse model and should be tested clinically. Supported by NIH grants RO1 CA78814 and RO1 CA87546 and Reata Pharmaceuticals, Inc.