Cancer chemopreventive properties of orally bioavailable flavonoids--methylated versus unmethylated flavones.
Poor oral bioavailability has been a major limitation for the successful use of dietary flavonoids as cancer chemopreventive agents. In this study, we examined fully methylated flavones as promising improved agents. In the human oral SCC-9 cancer cells, 5,7-dimethoxyflavone and 5,7,4'-trimethoxyflavone were both 10 times more potent inhibitors of cell proliferation (IC(50) values 5-8 microM) than the corresponding unmethylated analogs chrysin and apigenin. Flow cytometry indicated that both methylated flavones arrested the SCC-9 cells in the G1 phase with a concomitant decrease in the S phase, dramatically different from the unmethylated analogs, which promoted G2/M phase arrest. Both methylated compounds inhibited the proliferation of two other cancer cell lines with very little effect on two immortalized normal cell lines. Examination of additional flavone structures indicated that methylated flavones in general have antiproliferative properties. Finally, we demonstrated that 5,7-dimethoxyflavone, in contrast to its unmethylated analog chrysin, was well absorbed and had high oral bioavailability as well as tissue accumulation in vivo in the rat. Thus, fully methylated flavones appear to have great potential as cancer chemopreventive/chemotherapeutic agents, in particular in oral cancer.
Walle
Thomas
T
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA. wallet@musc.edu
Ta
Nga
N
Kawamori
Toshihiko
T
Wen
Xia
X
Tsuji
Petra A
PA
Walle
U Kristina
UK
D000818:Animals; D047310:Apigenin / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D047309:Flavones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005419:Flavonoids / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008745:Methylation; D051381:Rats; D011916:Rats, Inbred F344; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured
C427507:5,7,4'-trihydroxyflavone; D047309:Flavones; D005419:Flavonoids; C060298:5,7-dimethoxyflavone; C043561:chrysin; D047310:Apigenin