title: 5-Hydroxy-1,4-naphthalenedione exerts anticancer effects on glioma cells through interaction with the mitochondrial electron transport chain.
abstract: Survival of patients with glioblastoma remains within the range of several months despite advances in therapeutic options. We have already shown that 5-hydroxy-1,4-naphthalenedione (juglone) exerts antiproliferative, anti-invasive, and cytotoxic effects on glioma C6 cells. Here, we further revealed that juglone is relatively selective to glioma cells as compared to the normal glial culture, and investigated its mechanisms of action. The incubation of glioma C6 cells with juglone generated high levels of reactive oxygen species (ROS). The produced ROS accounted for the anticancer effect of juglone as antioxidant N-acetylcysteine reduced both cytotoxic and antiproliferative activities of juglone. Furthermore, high resolution respirometry revealed that juglone decreased oxygen consumption mainly by affecting pyruvate/malate- and glutamate/malate-induced mitochondrial respiration. The inhibition of respiratory complex I by amytal decreased juglone-triggered generation of ROS and diminished its anticancer activity. Thus, our results indicate that juglone generates ROS through interaction with respiratory complex I in glioma C6 cells, and, in turn, induces the anticancer effects.
authors.affiliation: Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania; Division of Neuropathology, Institute of Neurology, University College London, UK. Electronic address: kastytis.sidlauskas.11@ucl.ac.uk.
authors.forename: Kastytis
authors.initials: K
authors.lastname: Sidlauskas
authors.affiliation: Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Ruta
authors.initials: R
authors.lastname: Sidlauskiene
authors.affiliation: Division of Neuropathology, Institute of Neurology, University College London, UK.
authors.forename: Ningning
authors.initials: N
authors.lastname: Li
authors.affiliation: Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Julius
authors.initials: J
authors.lastname: Liobikas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004579:Electron Transport / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D009285:Naphthoquinones / Q000494:pharmacology*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C005134:juglone
keywords: Electron transport chain; Glioma; Juglone; Oxidative phosphorylation; Reactive oxygen species