Growth inhibition by methylated flavonoids is proteasome inhibition-independent Free

A121

Flavonoids are polyphenolic compounds that are widely distributed in the plant kingdom. Compelling research indicates that flavonoids have important roles in cancer chemoprevention and chemotherapy possibly due to biological activities that include action through anti-inflammation, free radical scavenging, modulation of survival/proliferation pathways, and proteasome inhibition. Plant polyphenols including the green tea polyphenol, (-)-EGCG, and the flavonoids apigenin, luteolin, quercetin, and chrysin have been shown to inhibit proteasome activity and induce apoptosis. However, biotransformation reactions on the reactive hydroxyl groups of polyphenols may reduce their biological activities. In the current study, methylated and unmethylated flavonoids were studied for their proteasome-inhibitory and growth-inhibitory abilities in human leukemia HL60 cells. Methylated flavonoids displayed sustained bioavailability and inhibited cellular proliferation by arresting cells in the G₁ phase. However, they did not act as proteasome inhibitors and only weakly induced apoptosis. In contrast, unmethylated flavonoids exhibited inhibition of the proteaosmal activity in intact HL60 cells, accumulating proteasome target proteins and inducing caspase activation and poly (ADP-ribose) polymerase cleavage. We conclude that methylated flavonoids lack potent cytotoxicity against human leukemia cancer cells and most likely have limited ability as chemopreventive agents.