An anticancer/cytotoxic activity of resveratrol is not hampered by its ability to induce the expression of the antioxidant/cytoprotective heme oxygenase-1 in RAW264.7 cells

Resveratrol, a polyphenol in red wine, exerts a cytotoxic activity and, also, it has a cytoprotective property, as a result of its ability to induce the expression of cytoprotective enzymes, including heme oxygenase-1 (HO-1). We examined whether a cytotoxic activity of resveratrol would be hampered by its ability to induce HO-1 expression. In RAW264.7 cells, resveratrol reduced cell viability by apoptosis; under our experimental conditions, an evident toxic activity was observed at 80 μM. At this cytotoxic dose, a remarkable expression of HO-1 was also observed. Both reduction of cell viability and expression of HO-1 correlated with reactive oxygen species (ROS) formation. Surprisingly, in the cells transfected with HO-1 small interfering RNA, a significant effect on cell viability was not observed after resveratrol treatment. Nevertheless, HO-1 expression prior to exposure to resveratrol significantly attenuated resveratrol-induced cytotoxicity. The mechanism for cytoprotection offered by a prior expression of HO-1 involved the inhibition of ROS formation. HO-1 expression following resveratrol treatment, however, had no effect on resveratrol-induced ROS formation. Taken together, our results suggest that the timing of HO-1 expression is important for its protection; HO-1 expression that occurs following treatment with a cytotoxic dose of resveratrol is not protective against resveratrol-induced cytotoxicity.