Topoisomerase II inhibition and high yield of endoreduplication induced by the flavonoids luteolin and quercetin

Luteolin and quercetin are widely distributed plantflavonoids that possess a variety of chemical and biologicalactivities, including free-radical scavenging and antio-xidant activity. Recently, both flavonoids have beenreported to inhibit DNA topoisomerases I and II (topo Iand topo II), a property that, together with their ability toinduce DNA and chromosome damage, has made themcandidate anticancer compounds. In the present study, weconfirmed that both compounds are topo II inhibitors byconducting a comparative study of their effect on topo IIactivity from Chinese hamster ovary AA8 cells. Becauseinterference with the function of topo II to resolve DNAentanglement at the end of replication results in chromo-some malsegregation at mitosis, we investigated whetherluteolin and quercetin are effective in inducing endo-reduplication in AA8 cells. Concentrations of luteolin andquercetin that inhibited topo II catalytic activity resultedin extraordinarily high yields of metaphases showingdiplochromosomes. Given the established relationship ofpolyploidy with tumor development via aneuploidy andgenetic instability, these results question the usefulness ofluteolin and quercetin in cancer therapy.IntroductionFlavonoids have a variety of biological and chemicalproperties. These compounds, widely distributed in the plantkingdom, are strong antioxidants (1,2) and have antimicrobial(3), anti-inflammatory/anti-allergic (4) antimutagenic (5),anticlastogenic (6) and anticarcinogenic properties (7,8). Dueto their function as antioxidants, flavonoids are included,together with b-carotene and vitamins C and E, among theradioprotective molecules present in human diets that are richin fruits and vegetables (9). These antioxidants may play animportant role in scavenging free radicals, such as the highlyreactive DNA-damaginghydroxylradicals inducedbyionizingradiation as a result of the radiolysis of water. Nevertheless,these reports of the beneficial effects of flavonoids arecounterbalanced somewhat by studies indicating that flavo-noids can induce DNA damage (10,11), mutations (12) andapoptosis (11,13).Luteolin and quercetin are bioactive flavonoids that areclosely related chemically (Figure 1). Both flavonoids protectagainstH