Evodiamine sensitizes U87 glioblastoma cells to TRAIL via the death receptor pathway

The tumor necrosis factor--related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce death in cancer cells without affecting healthy cells. Most glioma cells are resistant to TRAIL-induced apoptosis. Resistance to TRAIL limits its potential use as a drug for therapy of glioma. The present study was conducted to identify bioactive compounds that have the potential to sensitize U87 glioblastoma cells to TRAIL. Evodiamine, a major bioactive compound of the Chinese herb Evodiae fructus, has been reported to sensitize U87 glioblastoma cells to TRAIL. TRAIL and evodiamine, in combination or alone, were used to treat U87 glioblastoma cells. We show that evodiamine treatment inhibited cell growth in a dose-dependent manner; however, TRAIL alone failed to exert any cytotoxic effect. Combining TRAIL with evodiamine significantly increased the apoptotic rate of U87 glioblastoma cells, as compared to evodiamine treatment alone. Further investigation of the mechanism underlying these effects revealed that the evodiamine + TRAIL effect is associated with the increased expression of death receptor (DR)4, DR5, caspase-8 and cleaved caspase-3. The present study demonstrated, for the first time to the best of our knowledge, that evodiamine can sensitize U87 glioblastoma cells to TRAIL via the death receptor pathway. Thus, our results suggest that combined treatment with evodiamine and TRAIL may represent a novel chemotherapeutic strategy for the therapy of glioma.