Comparison of Anti-proliferative and Anti-inflammatory Effects of Nobiletin and Its Urinary Metabolite, 3′,4′-Didemethylnobiletin Check Access

Nobiletin is a polymethoxyflavone (PMF) present in citrus fruits, particularly in the peel. Our previous studies have identified that 3′,4′-didemethylnobiletin (DDMN) is one of the major metabolites of nobiletin in mouse urine and it has been shown to exhibit anti-inflammatory and anti-tumor promoting activity. In this study, we investigated the anti-proliferative and anti-inflammatory properties of these two compounds. The results demonstrated that both nobiletin and DDMN were able to induce cytotoxicity, cell cycle arrest and apoptosis in COLO205 cancer cells. Nobiletin showed a better activity on inducing apoptosis than its metabolite DDMN. In addition, treatment with nobiletin resulted in G1 phase cell cycle arrest, whereas DDMN caused G2/M phase arrest in COLO205 cancer cells. In anti-inflammatory analysis, DDMN showed a greater activity on inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in murine RAW264.7 macrophage. These results suggest that the anti-proliferative and anti-inflammatory activities of nobiletin and DDMN may undergo different mechanism.