ABSTRACT
1 Department of Biochemical and Pharmaceutical Sciences , University of Salerno, Italy
2 MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh Medical School, Edinburgh, UK
3Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
Glioblastoma multiforme (GBM) is the most common malignant and resistant tumor of the central nervous system in humans and new therapeutic strategies are urgently required (1). We have investigated the effect of the biologically active prenylated chalcone from Humulus Lupulus L. and potential anti-cancer agent xanthohumol (XH) (2), on apoptosis of human malignant glioblastoma cell line T98G. XH decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. XH-induced apoptosis was associated with activation of caspase-3, caspase-9 and PARP cleavage. Moreover we found how the apoptosis induced by XH was mediated by the mitochondrial pathway exemplified by mitochondria depolarization, cythocrome c release and downregulation of anti-apoptotic Bcl-2 protein. Importantly, we show that XH induces intracellular reactive oxygen species (ROS), an effect that was significantly reduced by pretreatment with the antioxidant N-Acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after XH exposure. Oxidative stress due to XH treatment is associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. We showed that phosphorylation of ERK1/2 and p38 was significantly attenuated using NAC to inhibit ROS production. After XH treatment, ROS provide a specific environment that resulted in MAPK-induced cell death; this effect was reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that XH is a potential chemotherapeutic agent for the treatment of GBM.