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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.

Mikuła-Pietrasik J, Sosińska P, Murias M, Wierzchowski M, Brewińska-Olchowik M, Piwocka K, Szpurek D, Książek K - Oxid Med Cell Longev (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Poznan University of Medical Sciences, Rokietnicka 8 Street, 60-806 Poznan, Poland.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of RVT and 3,3′,4,4′-THS on the activity of p38 MAPK in ovarian cancer cells. The level of enzyme activity upon cancer cell treatment with stilbenes for 24 h was estimated according to the ratio of phosphorylated to total p38 MAPK. The asterisks indicate a significant difference as compared to the control group. The hashes indicate a significant difference as compared to cells subjected to RVT. The experiments were performed in hexaplicate.
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fig7: Effect of RVT and 3,3′,4,4′-THS on the activity of p38 MAPK in ovarian cancer cells. The level of enzyme activity upon cancer cell treatment with stilbenes for 24 h was estimated according to the ratio of phosphorylated to total p38 MAPK. The asterisks indicate a significant difference as compared to the control group. The hashes indicate a significant difference as compared to cells subjected to RVT. The experiments were performed in hexaplicate.

Mentions: The p38 MAP kinase pathway (p38 MAPK) is one of the major signaling mechanisms that is involved in oxidative stress-mediated apoptosis [21] and cellular senescence [22]. In order to find if this is also the case with regard to apoptosis and senescence of ovarian cancer cells, activation of the enzyme via phosphorylation upon treatment with RVT and 3,3′,4,4′-THS was examined. The study showed that, in A2780 cells, RVT increased the activity of p38 MAPK at 100 μM, while 3,3′,4,4′-THS elicited its stimulatory activity at 50 and 100 μM. The effects of this compound were stronger as compared to RVT (Figure 7(a)). In OVCAR-3 and SKOV-3 cells, RVT failed to activate p38 MAPK, while 3,3′,4,4′-THS exerted upregulatory activity at 50 and 100 μM (Figures 7(b) and 7(c)).


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.

Mikuła-Pietrasik J, Sosińska P, Murias M, Wierzchowski M, Brewińska-Olchowik M, Piwocka K, Szpurek D, Książek K - Oxid Med Cell Longev (2015)

Effect of RVT and 3,3′,4,4′-THS on the activity of p38 MAPK in ovarian cancer cells. The level of enzyme activity upon cancer cell treatment with stilbenes for 24 h was estimated according to the ratio of phosphorylated to total p38 MAPK. The asterisks indicate a significant difference as compared to the control group. The hashes indicate a significant difference as compared to cells subjected to RVT. The experiments were performed in hexaplicate.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4502315&req=5

fig7: Effect of RVT and 3,3′,4,4′-THS on the activity of p38 MAPK in ovarian cancer cells. The level of enzyme activity upon cancer cell treatment with stilbenes for 24 h was estimated according to the ratio of phosphorylated to total p38 MAPK. The asterisks indicate a significant difference as compared to the control group. The hashes indicate a significant difference as compared to cells subjected to RVT. The experiments were performed in hexaplicate.
Mentions: The p38 MAP kinase pathway (p38 MAPK) is one of the major signaling mechanisms that is involved in oxidative stress-mediated apoptosis [21] and cellular senescence [22]. In order to find if this is also the case with regard to apoptosis and senescence of ovarian cancer cells, activation of the enzyme via phosphorylation upon treatment with RVT and 3,3′,4,4′-THS was examined. The study showed that, in A2780 cells, RVT increased the activity of p38 MAPK at 100 μM, while 3,3′,4,4′-THS elicited its stimulatory activity at 50 and 100 μM. The effects of this compound were stronger as compared to RVT (Figure 7(a)). In OVCAR-3 and SKOV-3 cells, RVT failed to activate p38 MAPK, while 3,3′,4,4′-THS exerted upregulatory activity at 50 and 100 μM (Figures 7(b) and 7(c)).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Poznan University of Medical Sciences, Rokietnicka 8 Street, 60-806 Poznan, Poland.

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.

No MeSH data available.


Related in: MedlinePlus