title: Quercetin-3-O-glucoside induces human DNA topoisomerase II inhibition, cell cycle arrest and apoptosis in hepatocellular carcinoma cells.
abstract: BACKGROUND
  Dietary flavonoids have been associated with reduced risk of cancer including hepatocellular carcinoma (HCC). Quercetin-3-O-glucoside (Q3G) has been shown to possess anti-proliferative and antioxidant activities. The objectives of this study were to assess the anti-proliferative properties of Q3G in human liver cancer cells (HepG2); assess the cytotoxicity on normal primary cells; and elucidate its possible mechanism of action(s).
  
  
  METHODS
  Using a dose- and time-dependent study, we evaluated the antiproliferative properties of Q3G in HepG2 cells using MTS cell viability assay and lactate dehydrogenase release assay. To elucidate the mechanism of action, we performed cell-cycle analysis using flow cytometry. Cell death via apoptosis was analyzed by DNA fragmentation assay, caspase-3 induction assay and fluorescence microscopy. DNA topoisomerase II drug screening assay was performed to assess the effect of Q3G on DNA topoisomerase II.
  
  
  RESULTS
  Q3G treatment inhibited cell proliferation in a dose- and time-dependent manner in HepG2 cells with the blockade of the cell cycle in the S-phase. Additionally, Q3G exhibited a strong ability to inhibit DNA topoisomerase II. Furthermore, DNA fragmentation and fluorescence microscopy analysis suggested that Q3G induced apoptosis in HepG2 cells with the activation of caspase-3. Interestingly, Q3G exhibited significantly lower toxicity to normal cells (primary human and rat hepatocytes and primary lung cells) than sorafenib (p<0.05), a chemotherapy drug for hepatocellular carcinoma. The results suggest that Q3G is a potential antitumor agent against liver cancer with a possible mechanism of action via cell-cycle arrest and apoptosis. Further research should be performed to confirm these results in vivo.
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, P.O Box 550, Truro, Nova Scotia B2N 5E3, Canada. vrupasinghe@dal.ca.
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Sudan
authors.forename: H P Vasantha
authors.initials: HP
authors.lastname: Rupasinghe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology* / Q000633:toxicity; D005960:Glucosides; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D011794:Quercetin / Q000031:analogs & derivatives; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D005960:Glucosides; D059005:Topoisomerase II Inhibitors; C532085:quercetin 3'-O-glucoside; D011794:Quercetin; D004250:DNA Topoisomerases, Type II
keywords: HepG2 cells; Quercetin-3-O-glucoside; apoptosis; cancer; caspase-3; cell cycle; topoisomerase II