Resveratrol analogue 3,4,4',5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV-3 and A-2780 cancer cells.
In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4'5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC(50)=0.71 μM) and SKOV-3 (IC(50)=11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212.
Department of Toxicology, Poznan University of Medical Sciences, Poznan, Poland.
Hanna
H
Piotrowska
Krzysztof
K
Myszkowski
Alicja
A
Ziółkowska
Katarzyna
K
Kulcenty
Marcin
M
Wierzchowski
Mariusz
M
Kaczmarek
Marek
M
Murias
Eliza
E
Kwiatkowska-Borowczyk
Jadwiga
J
Jodynis-Liebert
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1 / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000235:genetics
C482492:3,4,5,4'-tetramethoxystilbene; C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D013267:Stilbenes; D051028:bcl-2-Associated X Protein