Effects of Hydroxy Groups in the A-Ring on the Anti-proteasome Activity of Flavone

Abstract

The ubiquitin-proteasome pathway plays an important role in regulating apoptosis and the cell cycle. Recently, proteasome inhibitors have been shown to have antitumor effects and have been used in anticancer therapy for several cancers such as multiple myeloma. Although some flavones, such as apigenin, chrysin and luteolin, have a specific role in the inhibition of proteasome activity and induced apoptosis in some reports, these findings did not address all flavone types. To further investigate the proteasome-inhibitory mechanism of flavonoids, we examined the inhibitory activity of 5,6,7-trihydroxyflavone, baicalein and 5,6,7,4′-tetrahydroxyflavone, scutellarein on extracted proteasomes from mice and cancer cells. Unlike the other flavones, baicalein and scutellarein did not inhibit proteasome activity or accumulate levels of ubiquitinated proteins. These results indicate that flavones with hydroxy groups at positions 5, 6 and 7 of the A-ring lack the antiproteasome function. Key words ubiquitin; flavonoid; proteasome; inhibitorThe ubiquitin-proteasome pathway has an important role in regulating the cell cycle and apoptosis.1) This pathway involves two steps: (i) conjugation of multiple ubiquitin molecules to the target protein, and (ii) degradation of the ubiquitin-tagged protein by the 26S proteasome. The latter is a multi-subunit protease complex comprising a 20S core associated with two 19S regulatory caps. The 20S core particle is cylindrical and consists of two outer heptameric rings of α-subunits and two inner heptameric rings of β-subunits. The three main catalytic activities of proteasomes are associated with the 20S core. They are peptidylglutamyl peptide hydrolyzing (PGPH) activity (mediated by the β1 subunit), trypsin-like (T-L) activity (mediated by the β2 subunit), and chymotrypsin-like (CT-L) activity (mediated by the β5 subunit). 2)Flavonoids are a group of polyphenolic substances that are widely distributed in plants, fruits vegetables, tea and wine. Flavonoids reportedly have pharmacological effects that include antioxidant, antitumor, antiviral and anti-inflammatory activities. [3][4][5][6][7][8] Recent studies have shown that certain flavonoids can inhibit proteasome activity and induce apoptosis in tumor cells, which suggests that flavonoids have potential as a new type of anticancer drugs.9,10) However, not all flavonoids are strong inhibitors of the proteasome. Their proteasomal inhibitiory potency is dependent upon their chemical structure. Some flavones (e.g., luteolin, apigenin) are markedly more potent than other flavonoids such as flavonols (e.g., kaempferol), or flavanones (e.g., naringenin and eriodictyol).11) Flavonoid glycoside is one type of flavonoids, and some flavonoid glycosides, such as baicalin and scutellarin, reportedly affect the inhibition of proteasomes. 12) Flavones have been shown to have structure-activity relationships; the apoptosis-inducing potencies in tumor cells and inhibitory potencies in 20S purified proteasome were luteolin> apigenin>chrysin.11) Furthermor...

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“…36 Luteolin inhibited both chymotrypsinand trypsin-like catalytic activities in a dose-dependent manner and act weakly on caspase-like activity in all extracted 26S proteasomes from the liver of mice, HCT-116, and Jurkat cells. 38 Bo + Lu shows better inhibition than luteolin on 20S activity in vitro (Figure 1E).…”

“…morifolium. , Natural borneol could improve the oral bioavailability of some poorly permeable drugs by modulating the permeability of intestinal mucous or the blood–brain barrier . Luteolin inhibited both chymotrypsin- and trypsin-like catalytic activities in a dose-dependent manner and act weakly on caspase-like activity in all extracted 26S proteasomes from the liver of mice, HCT-116, and Jurkat cells . Bo + Lu shows better inhibition than luteolin on 20S activity in vitro (Figure E).…”