title: 3'-hydroxy-3,4,5,4'-tetramethoxystilbene, the metabolite of resveratrol analogue DMU-212, inhibits ovarian cancer cell growth in vitro and in a mice xenograft model.
abstract: In screening studies, the cytotoxic activity of four metabolites of resveratrol analogue 3,4,5,4'-tetramethoxystilbene (DMU-212) against A-2780 and SKOV-3 ovarian cancer cells was investigated. The most active metabolite, 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214), was chosen for further studies. The cytotoxicity of DMU-214 was shown to be higher than that of the parent compound, DMU-212, in both cell lines tested. Since DMU-212 was supposed to undergo metabolic activation through its conversion to DMU-214, an attempt was made to elucidate the mechanism of its anti-proliferative activity. We found that in SKOV-3 cells lacking p53, DMU-214 induced receptor-mediated apoptosis. In A-2780 cell line with expression of wild-type p53, DMU-214 modulated the expression pattern of p53-target genes driving intrinsic and extrinsic apoptosis pathways, as well as DNA repair and damage prevention. Regardless of the up-regulation of p48, p53R2, sestrins and Gaad45 genes involved in cancer cell DNA repair, we demonstrated the stronger anti-proliferative and pro-apoptotic effects of DMU-214 in A-2780 cells when compared to those in SKOV-3. Hence we verified DMU-214 activity in the xenograft model using SCID mice injected with A-2780 cells. The strong anti-proliferative activity of DMU-214 in the in vivo model allowed to suggest the tested compound as a potential therapeutic in ovarian cancer treatment.
authors: Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30 St., PL-60-631 Poznan, Poland.
authors: Hanna
authors: H
authors: Piotrowska-Kempisty
authors: Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St. PL-60-781 Poznan, Poland.
authors: Marcin
authors: M
authors: Ruciński
authors: Department of Anatomy, Poznan University of Medical Sciences, Swiecickiego 6 St., PL-61-781 Poznan, Poland.
authors: Sylwia
authors: S
authors: Borys
authors: Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30 St., PL-60-631 Poznan, Poland.
authors: Małgorzata
authors: M
authors: Kucińska
authors: Department of Clinical Immunology, Poznan University of Medical Sciences, Rokietnicka 5d St., PL-60-806 Poznan, Poland.
authors: Mariusz
authors: M
authors: Kaczmarek
authors: Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St. PL-60-781 Poznan, Poland.
authors: Piotr
authors: P
authors: Zawierucha
authors: Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6 St., PL-60-780 Poznan, Poland.
authors: Marcin
authors: M
authors: Wierzchowski
authors: Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6 St., PL-60-780 Poznan, Poland.
authors: Dawid
authors: D
authors: Łażewski
authors: Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30 St., PL-60-631 Poznan, Poland.
authors: Marek
authors: M
authors: Murias
authors: Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30 St., PL-60-631 Poznan, Poland.
authors: Jadwiga
authors: J
authors: Jodynis-Liebert
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015894:Genome, Human; D006801:Humans; D055442:Metabolome; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C482492:3,4,5,4'-tetramethoxystilbene; D000970:Antineoplastic Agents; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D000077185:Resveratrol