3'-Demethylnobiletin

The peels of Citrus nobilis Lour.

Suppressive effects of demethylated metabolites of nobiletin on phorbol ester-induced expression of scavenger receptor genes in THP-1 human monocytic cells.[Pubmed:18806314]

Biofactors. 2007;31(2):107-16.

Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs) is a key event in atherosclerosis. We previously reported that nobiletin (NOB), a citrus polymethoxylated flavone, markedly reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced SRs and adhesion molecules mRNA expression and blockade of DiI-acLDL uptake in THP-1 human monocyte-like cells. In this study, we examined the effects of NOB metabolites, 3'-hydroxy-5,6,7,8,4'-pentamethoxyflavone (3'-demethyl-NOB), 4'-hydroxy-5,6,7,8,3'-pentamethoxyflavone (4'-demethyl-NOB) and 3', 4'-dihydroxy-5,6,7,8,-tetramethoxyflavone (3', 4'-didemethyl-NOB) and NOB analog, tangeretin, on SRs and adhesion molecules mRNA expression. 3'-Demethyl-NOB significantly suppressed CD36 expression, moreover, 4'-demethyl- and 3', 4'-didemethyl-NOB significantly suppressed TPA-induced expression of SR-A and LOX-1. Further, the suppressive effects of 4'-demethyl- and 3', 4'-didemethyl-NOB on the expression of CD36 mRNA were greater extent than parent NOB. The inhibitory effects of the metabolites toward TPA-induced SR mRNA expression are partly associated with the suppression of AP-1 and NF-kappaB transcriptional activities. Together, our results suggest that metabolites of NOB, such as 4'-demethyl- and 3', 4'-didemethyl-NOB, have comparable or higher potentials to attenuate SR expression than NOB.

Chemopreventive effects of nobiletin and its colonic metabolites on colon carcinogenesis.[Pubmed:26445322]

Mol Nutr Food Res. 2015 Dec;59(12):2383-94.

SCOPE: Nobiletin (NBT) is a major citrus flavonoid with various health benefits. Herein, we investigated the colon cancer chemopreventive effects of NBT and its colonic metabolites in a colitis-associated colon carcinogenesis mouse model as well as in human colon cancer cell models. METHODS AND RESULTS: In azoxymethane/dextran sulfate sodium treated mice, oral administration of NBT effectively decreased both incidence and multiplicity of colonic tumors. NBT showed significant antiproliferative, proapoptotic, and anti-inflammatory effects in the mouse colon. HPLC analysis revealed that oral administration of NBT resulted in high levels of metabolites, i.e. 3'-demethylnobiletin (M1), 4'-demethylnobiletin (M2), and 3',4'-didemethylnobiletin (M3) in the colonic mucosa. In contrast, the colonic level of NBT was about 20-fold lower than the total colonic level of three metabolites. Cell culture studies demonstrated that the colonic metabolites of NBT significantly inhibited the growth of human colon cancer cells, caused cell-cycle arrest, induced apoptosis, and profoundly modulated signaling proteins related with cell proliferation and cell death. All of these effects were much stronger than those produced by NBT alone. CONCLUSION: Our results demonstrated that oral administration of NBT significantly inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly associated with its colonic metabolites.

3'-Demethylnobiletin, a derivative of Nobiletin, is a polymethoxyflavonoid in citrus fruits. Nobiletin exhibits anticancer activity and inhibits tumor angiogenesis by regulating Src, FAK, and STAT3 signaling.

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