Nobiletin is one of the most abundant polymethoxyflavones found in citrus fruits. Our results showed that nobiletin was transformed to 5-hydroxylnobiletin (N1) in rats after oral administration. Further metabolism of N1 produced 3�,5-dihydroxylnobiletin (N2), 4�,5-dihydroxylnobiletin (N3), and 3�,4�,5-trihydroxylnobiletin (N4). We chemically synthesized these metabolites, and investigated their inhibitory effects on human lung cancer cells. N1 showed 4- to 6-fold stronger inhibition on cancer cell growth than nobiletin. Interestingly, N2, N3, and N4, especially N2, were found to be even stronger than N1. The inhibition on cancer cells was associated with extensive cell cycle arrest and apoptosis (programmed cell death) caused by these metabolites as the result of modulation of oncogenic signaling proteins. Moreover, these metabolites were found to significantly inhibit tumorsphere formation of cancer stem cells. In conclusion, we demonstrated that in vivo biotransformation enhanced anti-cancer potential of nobiletin by transforming it to metabolites with much stronger anti-cancer activities.

Enhancing anti-carcinogenic effects of nobiletin by in vivo biotransformation

245th National Meeting (2013)

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