Cytotoxic, cytoprotective and antioxidant activities of resveratrol and analogues in C6 astroglioma cells in vitro.

Resveratrol (3,4',5-trans-trihydroxystilbene) and other hydroxystilbenes exhibit in vitro antioxidant as well as prooxidant effects. The antioxidant properties are assumed to enable these compounds to protect cells from oxidative damage. The prooxidant effects are held likely to be responsible for their cytotoxic, anti-proliferative or pro-apoptotic effects observed in vitro. Regarding antioxidant/prooxidant activities in the past various studies were performed aiming at defining structure-activity relationships for hydroxystilbenes using cell-free systems. In the present study cultured C6 glioma cells were used in order to investigate the relationship between the antioxidant, cytoprotective and cytotoxic activities of resveratrol and selected analogues, e.g., 3,3',4',5-trans-tetrahydroxystilbene (piceatannol), 3,3',5,5'-trans-tetrahydroxystilbene (3,3',5,5'-THS) and 3,3',4',5,5'-trans-pentahydroxystilbene (3,3',4',5,5'-PHS). All these compounds were cytotoxic to growth-arrested C6 cells, with EC50-values between 20 and 85 microM. A higher cytotoxic potency in proliferating cells indicated a specific cytostatic activity of resveratrol and 3,3',4',5,5'-PHS. All hydroxystilbenes studied inhibited cellular radical generation induced by cumene hydroperoxide (CHP). The rank order of antioxidant potency was resveratrol>piceatannol>3,3',5,5'-THS>3,3',4',5,5'-PHS. However, only resveratrol and piceatannol inhibited cellular radical generation at lower than cytotoxic concentrations. At subcytotoxic concentrations only piceatannol was able to protect the cells from damage caused by CHP. Taken together, these results show that neither the cytotoxic or cytostatic activities of hydroxystilbenes nor their cytoprotective and antioxidant activities in living cells can be predicted from their antioxidant and prooxidant activity, respectively, in cell-free systems.