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

Oxid Med Cell Longev. 2015:2015:135691. doi: 10.1155/2015/135691. Epub 2015 Jul 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Adult
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Catalase / metabolism
  • Catechols / chemistry
  • Catechols / toxicity*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Damage / drug effects*
  • DNA Glycosylases / metabolism
  • DNA Repair / drug effects
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / chemistry
  • Deoxyguanosine / metabolism
  • Female
  • Humans
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Oxidative Stress / drug effects*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / toxicity
  • Reactive Oxygen Species / metabolism
  • Resveratrol
  • Stilbenes / chemistry
  • Stilbenes / toxicity*
  • Superoxide Dismutase / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 3,3',4,4'-tetrahydroxystilbene
  • Catechols
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Stilbenes
  • 8-Hydroxy-2'-Deoxyguanosine
  • Catalase
  • Superoxide Dismutase
  • p38 Mitogen-Activated Protein Kinases
  • DNA Glycosylases
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Deoxyguanosine
  • Resveratrol