5-demethylnobiletin and Carcinogenesis

The intake of common polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), is strongly correlated to the initiation of colon cancer. BaP is a well-known pro-carcinogen that is metabolically activated by xenobiotic-metabolizing enzymes. Studies indicate that polymethoxyflavones, including 5-demethylnobiletin (5-DMNB), exhibit anti-inflammatory and anti-carcinogenic properties. However, the effects of 5-DMNB on xenobiotic-metabolizing enzymes and BaP-induced carcinogenesis remain unclear. The combination of BaP and a promoting agent-dextran sulfate sodium (DSS)-has been demonstrated to induce tumors in mouse models. Thus, this study aimed to determine the protective effect of 5-DMNB on carcinogen biotransformation and BaP/DSS-induced colon carcinogenesis. Our results showed that 5-DMNB had a substantial inhibitory effect on CYP1B1 induced by BaP and upregulated the detoxification enzymes UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs). Furthermore, subsequent analyses confirmed that the dietary administration of 5-DMNB markedly ameliorated tumor formation in BaP/DSS-treated mice. Exposure to BaP/DSS also significantly elevated TNF-α levels, and the administration of 5-DMNB reversed this increase. Taken together, we determined that 5-DMNB attenuates BaP/DSS-induced colon cancer through the regulation of inflammation and xenobiotic-metabolizing enzymes. These results indicate that 5-DMNB has significant potential as a novel chemopreventive agent for preventing carcinogen activation and inflammation-associated carcinogenesis.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Benzo(a)pyrene; Carcinogenesis; Colon; Colonic Neoplasms; Cytochrome P-450 CYP1B1; Dextran Sulfate; Flavones; Glucuronosyltransferase; Glutathione Transferase; Hep G2 Cells; Humans; Male; Mice, Inbred BALB C; Mice, Inbred ICR

5-Demethylnobiletin (5DN) is a unique citrus flavonoid with various beneficial bioactivities. In this study, we determined the inhibitory effects of 5DN and its two major metabolites in the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis mouse model as well as in human and mouse lung cancer cell models. In NNK-treated female A/J mice, dietary administration of 5DN (0.025% or 0.05% w/w in the diet) significantly decreased both lung tumor multiplicity and tumor volume. Immunohistochemical analysis showed strong anti-proliferative effects of 5DN in lung tumors. Two major metabolites of 5DN, named 5,3'-didemethylnobiletin (M1) and 5,4'-didemethylnobiletin (M2), were found in the lung tissue of 5DN-fed mice. Cell culture studies demonstrated that 5DN, M1 and M2 significantly inhibited the growth of human and mouse lung cancer cells by causing cell cycle arrest, inducing apoptosis and modulating key signaling proteins related to cell proliferation and cell death. Interestingly, the metabolites of 5DN, especially M1 produced much stronger inhibitory effects on both human and mouse lung cancer cells than those produced by 5DN itself. Our results demonstrated that dietary administration of 5DN significantly inhibited NNK-induced tumorigenesis in mice, and this effect may be partially associated with the metabolites of 5DN in lung tissues.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Carcinogenesis; Carcinogens; Citrus; Female; Flavones; Humans; Lung; Lung Neoplasms; Mice; Nitrosamines; Tobacco Products