Abstract
Glioblastoma multiforme (GBM) is an extremely aggressive and devastating malignant tumor in the central nervous system. Its incidence is increasing and the prognosis is poor. Artocarpin is a natural prenylated flavonoid with various anti-inflammatory and anti-tumor properties. Studies have shown that artocarpin is associated with cell death of primary glioblastoma cells. However, the in vivo effects and the cellular and molecular mechanisms modulating the anticancer activities of artocarpin remain unknown. In this study, we demonstrated that treating the glioblastoma cell lines U87 and U118 cells with artocarpin induced apoptosis. Artocarpin-induced apoptosis is associated with caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage and is mediated by the mitochondrial pathway. This is associated with mitochondrial depolarization, mitochondrial-derived reactive oxidative species (ROS) production, cytochrome c release, Bad and Bax upregulations, and Bcl-2 downregulation. Artocarpin induced NADPH oxidase/ROS generation plays an important role in the mitochondrial pathway activation. Furthermore, we found artocarpin-induced ROS production in mitochondria is associated with Akt- and ERK1/2 activation. After treatment with artocarpin, ROS causes PI3K/Akt/ERK1/2-induced cell death of these tumor cells. These observations were further verified by the results from the implantation of both U87 and U118 cells into in vivo mouse. In conclusion, our findings suggest that artocarpin induces mitochondria-associated apoptosis of glioma cells, suggesting that artocarpine can be a potential chemotherapeutic agent for future GBM treatment.
Highlights
Malignant glioma is the most common and lethal primary tumor of the central nervous system
We investigated the effects of artocarpin on caspase-3, -7, and -9 activities in U87- and U118 cells
We showed that artocarpin-induced Reactive oxygen species (ROS) production was effectively attenuated by pretreating U87 cells with MitoTEMPOL, diphenyleneiodonium chloride (DPI) (NADPH oxidase inhibitor), APO, FIGURE 2 | Artocarpin-induced apoptosis in U87- or U118 cells is mediated by ROS generation. (A) Cells were treated with artocarpin (10 μM) for the indicated times
Summary
Malignant glioma is the most common and lethal primary tumor of the central nervous system. Despite substantial advances in cancer treatment, mainly surgical resection followed by chemotherapy and adjuvant radiation therapy (Juratli et al, 2013; Carlsson et al, 2014), GBM remains the most deadly form of brain tumor because of its location, the devastating nature, influence of the blood-brain barrier and therapeutic resistance (Alifieris and Trafalis, 2015). Various new treatment strategies, including immunotherapy, nanotechnology, and moleculartargeted therapy have emerged as potential therapeutic options. These treatment strategies still possess limited success and do not have a substantial clinical effect (Polivka et al, 2012; Bambury and Morris, 2014; Ung and Yang, 2015). Increasing efforts are being made to investigate tumor pathophysiology and the molecular mechanisms in order to optimize therapeutic outcomes
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