title: The cranberry flavonoids PAC DP-9 and quercetin aglycone induce cytotoxicity and cell cycle arrest and increase cisplatin sensitivity in ovarian cancer cells.
abstract: Cranberry flavonoids (flavonols and flavan-3-ols), in addition to their antioxidant properties, have been shown to possess potential in vitro activity against several cancers. However, the difficulty of isolating cranberry compounds has largely limited anticancer research to crude fractions without well-defined compound composition. In this study, individual cranberry flavonoids were isolated to the highest purity achieved so far using gravity and high performance column chromatography and LC-MS characterization. MTS assay indicated differential cell viability reduction of SKOV-3 and OVCAR-8 ovarian cancer cells treated with individual cranberry flavonoids. Treatment with quercetin aglycone and PAC DP-9, which exhibited the strongest activity, induced apoptosis, led to caspase-3 activation and PARP deactivation, and increased sensitivity to cisplatin. Furthermore, immunofluorescence microscopy and western blot study revealed reduced expression and activation of epidermal growth factor receptor (EGFR) in PAC DP-9 treated SKOV-3 cells. In addition, quercetin aglycone and PAC DP-9 deactivated MAPK-ERK pathway, induced downregulation of cyclin D1, DNA-PK, phospho-histone H3 and upregulation of p21, and arrested cell cycle progression. Overall, this study demonstrates promising in vitro cytotoxic and anti-proliferative properties of two newly characterized cranberry flavonoids, quercetin aglycone and PAC DP-9, against ovarian cancer cells.
authors.affiliation: Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ 08901, USA.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02905, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Han
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02905, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Chen
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02905, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Clinton O
authors.initials: CO
authors.lastname: Chichester
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02905, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
authors.affiliation: Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ 08901, USA.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ 08901, USA.
authors.forename: Nicholi
authors.initials: N
authors.lastname: Vorsa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000633:toxicity*; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002845:Chromatography; D002945:Cisplatin / Q000494:pharmacology*; D053938:DNA Fragmentation; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D020287:In Situ Nick-End Labeling; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D044945:Proanthocyanidins / Q000633:toxicity*; D011794:Quercetin / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D029799:Vaccinium macrocarpon / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D044945:Proanthocyanidins; C013221:proanthocyanidin; D004815:Epidermal Growth Factor; D011794:Quercetin; D020929:Mitogen-Activated Protein Kinase Kinases; D053148:Caspase 3; D002945:Cisplatin