title: Flavonoid-enriched apple fraction AF4 induces cell cycle arrest, DNA topoisomerase II inhibition, and apoptosis in human liver cancer HepG2 cells.
abstract: Apples are a major source of dietary phytochemicals such as flavonoids in the Western diet. Here we report anticancer properties and possible mechanism of action of apple flavonoid-enriched fraction (AF4) isolated from the peels of Northern Spy apples in human hepatocellular carcinoma cells, HepG2. Treatment with AF4 induced cell growth inhibition in HepG2 cells in time- and dose-dependent manner. Concentration of 50 μg/ml (50 μg total monomeric polyphenols/ml) AF4 was sufficient to induce a significant reduction in cell viability within 6 h of treatment (92%, P < 0.05) but had very low toxicity (minimum 4% to maximum 16%) on primary liver and lung cells, which was significantly lower than currently prescribed chemotherapy drug Sorafenib (minimum 29% to maximum 49%, P < 0.05). AF4 induced apoptosis in HepG2 cells within 6 h of treatment via activation of caspase-3. Cell cycle analysis via flow-cytometer showed that AF4 induced G2/M phase arrest. Further, results showed that AF4 acts as a strong DNA topoisomerase II catalytic inhibitor, which may be a plausible reason to drive the cells to apoptosis. Overall, our data suggests that AF4 possesses a significantly stronger antiproliferative and specific action than Sorafenib in vitro and is a potential natural chemotherapy agent for treatment of liver cancer.
authors.affiliation: a Department of Environmental Sciences, Faculty of Agriculture , Dalhousie University , Truro , Nova Scotia , Canada.
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; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D027845:Malus / Q000737:chemistry*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D000077157:Sorafenib; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010671:Phenylurea Compounds; D059005:Topoisomerase II Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; C505407:CASP3 protein, human; D053148:Caspase 3; D004250:DNA Topoisomerases, Type II