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.
Highlights
Resveratrol (3,4′,5-trans-trihydroxystilbene) has widely been studied for its anti-bacterial, anti-fungal, anti-inflammatory, anti-oxidative and anti-cancer effects[1,2]
The inhibitory effect of four metabolites tested against the A-2780 and SKOV-3 cell lines was evaluated after 24 h, 48 h and 72 h at a concentration of 10 μM by MTT assay (Table 1)
We evaluated the cytotoxicity of four metabolites of DMU-212 in A-2780 and SKOV-3 human ovarian cancer cell lines
Summary
Resveratrol (3,4′,5-trans-trihydroxystilbene) has widely been studied for its anti-bacterial, anti-fungal, anti-inflammatory, anti-oxidative and anti-cancer effects[1,2]. The analysis of the structure-activity relationships showed that the introduction of additional methoxy groups into the stilbene backbone potentiated the cytotoxic effects of the compound. Moiety have been reported to demonstrate stronger pro-apoptotic activity when compared to other stilbene derivatives[5]. One such molecule, DMU-212 (3,4,5,4′-tetramethoxystilbene), has been revealed to have anti-cancer activity via cell cycle arrest and activation of apoptosis[6,7,8,9,10,11,12]. The aim of the present study was to evaluate the molecular mechanism of the potential anti-proliferative activity of DMU-214 in A-2780 and SKOV-3 ovarian cancer cell lines. Since the A-2780 cell line was found to be more sensitive to DMU-214 than SKOV-3, the anti-tumour properties of the compound tested in vivo were investigated using SCID mice injected with A-2780 cells
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