Structurally related flavonoids with antioxidative properties differentially affect cell cycle progression and apoptosis of human acute leukemia cells

Flavonoids are a group of common phenolic compounds that are ubiquitous in all vascular plants and are important constituents of the human diet. The possible relationship between the chemical structure of 6 closely related naturally occurring flavonoids and their antioxidative properties as well as their effects on proliferation, apoptosis, and cycle of human acute leukemia (HL-60) cells were investigated. Quercetin, myricetin, kaempferol, and isorhamnetin were found to be potent antiproliferative agents, whereas 3 '-methylquercetagetin and taxifolin were ineffective indicating that the C2-C3 double bond and the 6-hydroxyl group are important structural requirements for the cytostatic effects of flavonoids. The analysis by low cytometry showed that quercetin and myricetin were the most potent apoptosis-inducing agents among the flavonoids tested. Myricetin, isorhamnetin, and kaempferol induced time- and concentration-dependent alterations in number of cells in G(0)/G(1) and S phase. Only quercetin increased the number of cells in G(2)/M phase. Myricetin showed the strongest scavenging activity against 1,1 '-diphenyl-2-picrilhydrazyl (DPPH) radicals among the flavonoids tested, but it was almost ineffective in reducing reactive oxygen species level in menadione-stressed HL-60 cells. Scavenging activity against DPPH radicals was dependent on the number of hydroxyl groups in the ring B of flavonoids. In contrast, kaempferol was the most effective reactive oxygen species scavenger in menadione-stressed cells. The presence of the 6-hydroxyl group was shown to be an unfavorable structural feature of flavonoids with regard to DPPH scavenging and antioxidative effects of flavonoids. Minor chemical differences between flavonoids tested produced significant differences concerning their effects on HL-60 cell proliferation and cycle distribution, apoptosis, or their antioxidant activity. (c) 2005 Elsevier Inc. All rights reserved.