Thymoquinone Inhibits Autophagy and Induces Cathepsin-Mediated, Caspase-Independent Cell Death in Glioblastoma Cells

摘要: Glioblastoma is the most aggressive and common type of malignant brain tumor in humans, with a median survival 15 months. There great need for more therapies treatment glioblastoma. Naturally occurring phytochemicals have received much scientific attention because many exhibit potent killing action. Thymoquinone (TQ) bioactive compound Nigella sativa seed oil. TQ has anti-oxidant, anti-inflammatory anti-neoplastic actions selective cytotoxicity human cancer cells compared to normal cells. Here, we show that selectively inhibits clonogenicity glioblastoma as astrocytes. Also, cell proliferation could be impaired by chloroquine, an autophagy inhibitor, suggesting may dependent on autophagic pathway survival. Exposure caused increase recruitment accumulation microtubule-associated protein light chain 3-II (LC3-II). also LC3-associated p62, confirming inhibition autophagy. Furthermore, levels Beclin-1 expression were unchanged, indicating interferes later stage Finally, induces lysosome membrane permeabilization, determined specific loss red acridine orange staining. Lysosome permeabilization resulted leakage cathepsin B into cytosol, which mediates caspase-independent death can prevented pre-treatment inhibitor. induced apoptosis, PI Annexin V positive However, apoptosis appears due failure caspase inhibitor z-VAD-FMK prevent absence typical related signature DNA fragmentation. Inhibition exciting emerging strategy therapy. In this vein, our results describe novel mechanism action targeting