Combination of Ascorbic Acid and Menadione Induces Cytotoxic Autophagy in Human Glioblastoma Cells

We investigated the ability of the ascorbic acid (AA) and menadione (MD) combination, the well-known reactive oxidative species- (ROS-) generating system, to induce autophagy in human U251 glioblastoma cells. A combination of AA and MD (AA+MD), in contrast to single treatments, induced necrosis-like...

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Published in:Oxidative medicine and cellular longevity 2022-03, Vol.2022, p.2998132-18
Main Authors: Despotović, Ana, Mirčić, Aleksandar, Misirlić-Denčić, Sonja, Harhaji-Trajković, Ljubica, Trajković, Vladimir, Zogović, Nevena, Tovilović-Kovačević, Gordana
Format: Article
Language:English
Subjects:
Adapter proteins
Apoptosis
Ascorbic Acid - pharmacology
Automation
Autophagy
Autophagy - physiology
Biosynthesis
Brain cancer
Cancer therapies
Cell culture
Cytotoxicity
Gene expression
Glioblastoma - drug therapy
Humans
Kinases
Microscopy
Oxidative stress
Phosphorylation
Prostate
TOR Serine-Threonine Kinases - metabolism
Vitamin K 3 - pharmacology
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Summary:We investigated the ability of the ascorbic acid (AA) and menadione (MD) combination, the well-known reactive oxidative species- (ROS-) generating system, to induce autophagy in human U251 glioblastoma cells. A combination of AA and MD (AA+MD), in contrast to single treatments, induced necrosis-like cell death mediated by mitochondrial membrane depolarization and extremely high oxidative stress. AA+MD, and to a lesser extent MD alone, prompted the appearance of autophagy markers such as autophagic vacuoles, autophagosome-associated LC3-II protein, degradation of p62, and increased expression of beclin-1. While both MD and AA+MD increased phosphorylation of AMP-activated protein kinase (AMPK), the well-known autophagy promotor, only the combined treatment affected its downstream targets, mechanistic target of rapamycin complex 1 (mTORC1), Unc 51-like kinase 1 (ULK1), and increased the expression of several autophagy-related genes. Antioxidant N-acetyl cysteine reduced both MD- and AA+MD-induced autophagy, as well as changes in AMPK/mTORC1/ULK1 activity and cell death triggered by the drug combination. Pharmacological and genetic autophagy silencing abolished the toxicity of AA+MD, while autophagy upregulation enhanced the toxicity of both AA+MD and MD. Therefore, by upregulating oxidative stress, inhibiting mTORC1, and activating ULK1, AA converts MD-induced AMPK-dependent autophagy from nontoxic to cytotoxic. These results suggest that AA+MD or MD treatment in combination with autophagy inducers could be further investigated as a novel approach for glioblastoma therapy.
ISSN:1942-0900
1942-0994
DOI:10.1155/2022/2998132