Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass?

Abstract

Dietary flavonoids and other polyphenols show great potential as cancer chemopreventive agents in cell culture studies. This does not translate well into in vivo activity, because of extensive conjugative metabolism of these compounds in the intestine and liver. This paper presents a review of a flavonoid subclass in which all hydroxyl groups are capped by methylation. This results in dramatically increased metabolic stability and membrane transport in the intestine/liver, thus improving oral bioavailability. The methoxyflavones also show increased cancer chemopreventive properties. At the cancer initiation stage, bioactivation of polyaromatic hydrocarbon carcinogens and binding to DNA are markedly diminished through effects on CYP1A1/1B1 transcription but also through direct interactions with the proteins. At the cancer promotion stage, the proliferation of cancer cells, but not normal cells, is inhibited with greater potency than with the unmethylated flavones. Limited mechanistic experiments, such as of effects on cell cycle regulation, indicate that the mechanisms of methoxyflavone activities are unique, including aromatase inhibition. The cancer preventive effects and mechanisms of the polymethoxyflavones, such as tangeretin and nobiletin, are discussed in comparison. It is concluded that the methoxyflavones have properties that may make them particularly useful as cancer chemopreventive agents.

Fig. 1

Structures of 5,7-dihydroxyflavone (chrysin) and 5,7-dimethoxyflavone (5,7-DMF).

Fig. 2

Plasma and tissue levels of 5,7-DMF and chrysin after oral administration of 5 mg/kg in rats; (A) Plasma 5,7-DMF (no chrysin could be detected at any time-point); (B) 5,7-DMF in post-absorption tissues, liver (○), lung (■) and kidney (Δ); (C) 5,7-DMF (□) and chrysin (●) in the proximal 2 cm of the colon with the associated fecal pellet. The data represent the mean ± SEM of 5 animals at each time-point. From [31].

Fig. 3

Effects of 5,7-DMF on BaP-induced CYP1A1 activity (A), CYP1A1 protein expression (B) and CYP1A1 mRNA level (C) in the Hep G2 cells and on recombinant CYP1A1 activity (D). A-C: Hep G2 cells were exposed for 6 hr to different concentrations of 5,7-DMF in the presence or absence of 1 μM BaP. D: Recombinant CYP1A1 was incubated with various concentrations of 5,7-DMF [37].

Fig. 4

Effect of 5,7,4′-TMF compared to the unmethylated analog apigenin on SCC-9 cell proliferation. Cell proliferation, expressed as percent of control (DMSO-treatment), was measured as BrdU incorporation into cellular DNA after a 24-h exposure of the cells to the flavones [31]. The numbers shown in the figure are the calculated IC₅₀ values. From [31]. * significantly lower than control, P < 0.05. # significantly higher than control, P < 0.05.