title: High Potency of a Novel Resveratrol Derivative, 3,3',4,4'-Tetrahydroxy-trans-stilbene, against Ovarian Cancer Is Associated with an Oxidative Stress-Mediated Imbalance between DNA Damage Accumulation and Repair.
abstract: We explored the effect of a new resveratrol (RVT) derivative, 3,3',4,4'-tetrahydroxy-trans-stilbene (3,3',4,4'-THS), on viability, apoptosis, proliferation, and senescence of three representative lines of ovarian cancer cells, that is, A2780, OVCAR-3, and SKOV-3, in vitro. In addition, the mechanistic aspects of 3,3',4,4'-THS activity, including cell redox homeostasis (the production of reactive oxygen species, activity of enzymatic antioxidants, and magnitude of DNA damage accumulation and repair), and the activity of caspases (3, 8, and 9) and p38 MAPK were examined. The study showed that 3,3',4,4'-THS affects cancer cell viability much more efficiently than its parent drug. This effect coincided with increased generation of reactive oxygen species, downregulated activity of superoxide dismutase and catalase, and excessive accumulation of 8-hydroxy-2'-deoxyguanosine and its insufficient repair due to decreased expression of DNA glycosylase I. Cytotoxicity elicited by 3,3',4,4'-THS was related to increased incidence of apoptosis, which was mediated by caspases 3 and 9. Moreover, 3,3',4,4'-THS inhibited cancer cell proliferation and accelerated senescence, which was accompanied by the activation of p38 MAPK. Collectively, our findings indicate that 3,3',4,4'-THS may constitute a valuable tool in the fight against ovarian malignancy and that the anticancer capabilities of this stilbene proceed in an oxidative stress-dependent mechanism.
authors.affiliation: Department of Pathophysiology, Poznan University of Medical Sciences, Rokietnicka 8 Street, 60-806 Poznan, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Mikuła-Pietrasik
authors.affiliation: Department of Pathophysiology, Poznan University of Medical Sciences, Rokietnicka 8 Street, 60-806 Poznan, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Sosińska
authors.affiliation: Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30 Street, 60-631 Poznan, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Murias
authors.affiliation: Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wierzchowski
authors.affiliation: Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Brewińska-Olchowik
authors.affiliation: Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piwocka
authors.affiliation: Division of Gynecological Surgery, Poznan University of Medical Sciences, Polna 33 Street, 60-535 Poznan, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Szpurek
authors.affiliation: Department of Pathophysiology, Poznan University of Medical Sciences, Rokietnicka 8 Street, 60-806 Poznan, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Książek
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002396:Catechols / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000606671:3,3',4,4'-tetrahydroxystilbene; D002396:Catechols; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002374:Catalase; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; D045647:DNA Glycosylases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D003849:Deoxyguanosine; D000077185:Resveratrol