Distinct mechanisms of DNA damage in apoptosis induced by quercetin and luteolin.
Quercetin has been reported to have carcinogenic effects. However, both quercetin and luteolin have anti-cancer activity. To clarify the mechanism underlying the carcinogenic effects of quercetin, we compared DNA damage occurring during apoptosis induced by quercetin with that occuring during apoptosis induced by luteolin. Both quercetin and luteolin similarly induced DNA cleavage with subsequent DNA ladder formation, characteristics of apoptosis, in HL-60 cells. In HP 100 cells, an H2O2-resistant clone of HL-60 cells, the extent of DNA cleavage and DNA ladder formation induced by quercetin was less than that in HL-60 cells, whereas differences between the two cell types were minimal after treatment with luteolin. In addition, quercetin increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an indicator of oxidative DNA damage, in HL-60 cells but not in HP 100 cells. Luteolin did not increase 8-oxodG formation, but inhibited topoisomerase II (topo II) activity of nuclear extract more strongly than quercetin and cleaved DNA by forming a luteolin-topo II-DNA ternary complex. These results suggest that quercetin induces H2O2-mediated DNA damage, resulting in apoptosis or mutations, whereas luteolin induces apoptosis via topo II-mediated DNA cleavage. The H2O2-mediated DNA damage may be related to the carcinogenic effects of quercetin.
Yamashita
N
N
Department of Hygiene, School of Medicine, Mie University, Tsu, Japan.
Kawanishi
S
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity*; D002457:Cell Extracts; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity; D005419:Flavonoids / Q000633:toxicity*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047311:Luteolin; D011794:Quercetin / Q000633:toxicity*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D002457:Cell Extracts; D004791:Enzyme Inhibitors; D005419:Flavonoids; D059005:Topoisomerase II Inhibitors; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011794:Quercetin; D006861:Hydrogen Peroxide; D004250:DNA Topoisomerases, Type II; D003849:Deoxyguanosine; D047311:Luteolin