title: Towards novel anti-tumor strategies for hepatic cancer: ɛ-viniferin in combination with vincristine displays pharmacodynamic synergy at lower doses in HepG2 cells.
abstract: Hepatocellular carcinoma is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. The efficacy of novel combination treatments are increasingly evaluated with use of integrative biology research and development (R&D) strategies and methodological triangulation. We investigated the anti-tumor effect of ɛ-viniferin alone, and the putative synergy of ɛ-viniferin with vincristine on the growth of HepG2 cells in vitro. Growth inhibition and apoptosis induction were determined by MTT assay and annexin V/propidium iodide (PI), respectively. Morphological changes and DNA fragmentation were investigated under electron microscopy and by agarose gel electrophoresis, respectively. The results collectively showed that treating cells with ɛ-viniferin and vincristine significantly inhibited cell viability at lower doses as compared to each agent applied alone. IC(50) values for ɛ-viniferin and vincristine were determined as 98.3 and 52.5 μM at 24 h, respectively. IC(50) value of ɛ-viniferin in combination with vincristine was 15.8+11.25 μM (mean/SD) at 24 h. The viability of cells treated with 17.9 μM vincristine alone for 24 h was 79.62%; it reduced to 26.53% when 25 μM ɛ-viniferin was added in combination with vincristine (p<0.05). We found that combination of drugs promoted the sensitivity of cells against to vincristine treatment. The effect of combined use was in support of a synergistic pharmacodynamic effect. Moreover, low doses of the combination regimen induced phosphatidyl re-localization, morphological changes, and DNA fragmentation, and therefore caused apoptotic death. This study thus suggests that low concentrations of ɛ-viniferin and vincristine can enhance the anti-tumor effects efficiently by inducing HepG2 cell apoptosis. Further studies in other model systems are warranted with a view to potential future applications in the clinic of such combination regimens and their putative mechanism of action in the observed synergy reported here.
authors.affiliation: 1 Faculty of Pharmacy, Department of Biochemistry, Anadolu University , Tepebası, Eskisehir, Turkey .
authors.forename: Filiz
authors.initials: F
authors.lastname: Özdemir
authors.forename: Gülşen
authors.initials: G
authors.lastname: Akalın
authors.forename: Mesut
authors.initials: M
authors.lastname: Şen
authors.forename: Nur Ipek
authors.initials: NI
authors.lastname: Önder
authors.forename: Arzu
authors.initials: A
authors.lastname: Işcan
authors.forename: H Mehtap
authors.initials: HM
authors.lastname: Kutlu
authors.forename: Zerrin
authors.initials: Z
authors.lastname: Incesu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001572:Benzofurans / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy*; D013267:Stilbenes / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; D013267:Stilbenes; D014750:Vincristine; C091891:epsilon-viniferin