title: Structure related effects of flavonoid aglycones on cell cycle progression of HepG2 cells: Metabolic activation of fisetin and quercetin by catechol-O-methyltransferase (COMT).
abstract: Dietary flavonoids are abundant in the Plant Kingdom and they are extensively studied because of their manifold pharmacological activities. Recent studies highlighted that cell cycle arrest plays a key role in their antiproliferative effect in different tumor cells. However, structure-activity relationship of flavonoids is poorly characterized. In our study the influence of 18 flavonoid aglycones (as well as two metabolites) on cell cycle distribution was investigated. Since flavonoids are extensively metabolized by liver cells, HepG2 tumor cell line was applied, considering the potential metabolic activation/inactivation of flavonoids. Our major observations are the followings: (1) Among the tested compounds diosmetin, fisetin, apigenin, lutelin, and quercetin provoked spectacular extent of G2/M phase cell cycle arrest. (2) Inhibition of catechol-O-methyltransferase enzyme by entacapone decreased the antiproliferative effects of fisetin and quercetin. (3) Geraldol and isorhamnetin (3'-O-methylated metabolites of fisetin and quercetin, respectively) demonstrated significantly higher antiproliferative effect on HepG2 cells compared to the parent compounds. Based on these results, O-methylated flavonoid metabolites or their chemically modified derivatives may be suitable candidates of tumor therapy in the future.
authors: Department of Pharmacology and Pharmacotherapy, Toxicology Section, University of Pécs, Szigeti út 12, Pécs H-7624, Hungary; Department of Laboratory Medicine, University of Pécs, Ifjúság út 13, Pécs H-7624, Hungary. Electronic address: poor.miklos@pte.hu.
authors: Miklós
authors: M
authors: Poór
authors: Department of Laboratory Medicine, University of Pécs, Ifjúság út 13, Pécs H-7624, Hungary.
authors: Zita
authors: Z
authors: Zrínyi
authors: Department of Laboratory Medicine, University of Pécs, Ifjúság út 13, Pécs H-7624, Hungary; János Szentágothai Research Center, Lab-on-a-chip Research Group, Ifjúság út 20, Pécs H-7624, Hungary.
authors: Tamás
authors: T
authors: Kőszegi
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D044948:Flavonols; D056945:Hep G2 Cells; D006801:Humans; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D011794:Quercetin / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C560847:3,4',7-trihydroxy-3'-methoxyflavone; D002396:Catechols; D047309:Flavones; D005419:Flavonoids; D044948:Flavonols; D009570:Nitriles; C071192:entacapone; D011794:Quercetin; D002394:Catechol O-Methyltransferase; C017875:fisetin
keywords: Catechol-O-methyltransferase; Cell cycle arrest; Flavonoid aglycones; Geraldol; Isorhamnetin