Menadione‐induced apoptosis in U937 cells involves Bid cleavage and stefin B degradation

Božič, Janja; Bidovec, Katja; Vizovišek, Matej; Dolenc, Iztok; Stoka, Veronika

doi:10.1002/jcb.28356

Cited by 5 publications

(3 citation statements)

References 40 publications

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“…Treatment with the ROS scavenger NAC almost completely restored cell viability (Fig. 5C), indicating that ROS production is the lethal mechanism induced by menadione in these experiments and not induction of apoptosis (Bozic, Bidovec, Vizovisek, Dolenc, & Stoka, 2019) or other mechanism. In contrast, inhibition of necroptosis by necrostatin-1s (RIPK1), GSK'872 (RIPK3) and necrosulfonamide (MLKL) did not prevent the cell death induced by menadione (Fig.…”

Section: Menadione-induced Ros Do Not Enhance Necroptosis By a Positive Feedback Loop In Macrophagesmentioning

confidence: 61%

NAD hydrolysis by the tuberculosis necrotizing toxin induces lethal oxidative stress in macrophages

Pajuelo

Niederweis

2019

Cellular Microbiology

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Mycobacterium tuberculosis (Mtb) kills infected macrophages through necroptosis, a programmed cell death that enhances mycobacterial replication and dissemination. The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mtb in macrophages and induces necroptosis by NAD + hydrolysis. Here, we show that the catalytic activity of TNT triggers the production of reactive oxygen species (ROS) in Mtb-infected macrophages causing cell death and promoting mycobacterial replication. TNT induces ROS formation both by activating necroptosis and by a necroptosis-independent mechanism. Most of the detected ROS originate in mitochondria as a consequence of opening the mitochondrial permeability transition pore. However, a significant part of ROS is produced by mechanisms independent of TNT and necroptosis. Expressing only the tnt gene in Jurkat T-cells also induces lethal ROS formation indicating that these molecular mechanisms are not restricted to macrophages. Both the antioxidant N-acetyl-cysteine and replenishment of NAD + by providing nicotinamide reduce ROS levels in Mtb-infected macrophages, protect them from cell death and restrict mycobacterial replication. Our results indicate that a host-directed therapy combining replenishment of NAD + with inhibition of necroptosis and/or antioxidants might improve the health status of TB patients and augment antibacterial TB chemotherapy.

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Section: Menadione-induced Ros Do Not Enhance Necroptosis By a Positive Feedback Loop In Macrophagesmentioning

confidence: 61%

NAD hydrolysis by the tuberculosis necrotizing toxin induces lethal oxidative stress in macrophages

Pajuelo

Niederweis

2019

Cellular Microbiology

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“…Menadione (2-methyl-1,4-naphthoquinone; MD, vitamin K3) is a lipid-soluble synthetic analog of vitamin K, metabolized by the human body into menaquinone (vitamin K2). Numerous studies showed potent anticancer activity of MD in various cancer cell lines, with both antiproliferative and direct cytotoxic action resulting in caspase-dependent [ 3 – 6 ], caspase-independent apoptosis [ 7 ], necroptosis [ 8 ], or necrosis-like cell death [ 9 ]. The main mechanism of MD cytotoxic action is closely related to reactive oxygen species (ROS) produced during its metabolism.…”

Section: Introductionmentioning

confidence: 99%

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

Despotović

Mirčić

Misirlić-Denčić

et al. 2022

Oxidative Medicine and Cellular Longevity

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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.

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“…U937 cells have the peculiarity to express many of the monocytic-like characteristics and were selected as a model cell line since autophagy plays an important role in acute leukemias [13], and in addition, this pathway seems to play a pivotal role in the growth and differentiation of this cell line [14]. Furthermore, the U937 cell line shows sensitivity to the drugs selected for this study [15–18].…”

Section: Introductionmentioning

confidence: 99%

Autophagy: A Player in response to Oxidative Stress and DNA Damage

Galati

Böni

Gerra

et al. 2019

Oxidative Medicine and Cellular Longevity

110

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Autophagy is a catabolic pathway activated in response to different cellular stressors, such as damaged organelles, accumulation of misfolded or unfolded proteins, ER stress, accumulation of reactive oxygen species, and DNA damage. Some DNA damage sensors like FOXO3a, ATM, ATR, and p53 are known to be important autophagy regulators, and autophagy seems therefore to have a role in DNA damage response (DDR). Recent studies have partly clarified the pathways that induce autophagy during DDR, but its precise role is still not well known. Previous studies have shown that autophagy alterations induce an increase in DNA damage and in the occurrence of tumor and neurodegenerative diseases, highlighting its fundamental role in the maintenance of genomic stability. During DDR, autophagy could act as a source of energy to maintain cell cycle arrest and to sustain DNA repair activities. In addition, autophagy seems to play a role in the degradation of components involved in the repair machinery. In this paper, molecules which are able to induce oxidative stress and/or DNA damage have been selected and their toxic and genotoxic effects on the U937 cell line have been assessed in the presence of the single compounds and in concurrence with an inhibitor (chloroquine) or an inducer (rapamycin) of autophagy. Our data seem to corroborate the fundamental role of this pathway in response to direct and indirect DNA-damaging agents. The inhibition of autophagy through chloroquine had no effect on the genotoxicity induced by the tested compounds, but it led to a high increase of cytotoxicity. The induction of autophagy, through cotreatment with rapamycin, reduced the genotoxic activity of the compounds. The present study confirms the cytoprotective role of autophagy during DDR; its inhibition can sensitize cancer cells to DNA-damaging agents. The modulation of this pathway could therefore be an innovative approach able to reduce the toxicity of many compounds and to enhance the activity of others, including anticancer drugs.

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Menadione‐induced apoptosis in U937 cells involves Bid cleavage and stefin B degradation

Cited by 5 publications

References 40 publications

NAD hydrolysis by the tuberculosis necrotizing toxin induces lethal oxidative stress in macrophages

NAD hydrolysis by the tuberculosis necrotizing toxin induces lethal oxidative stress in macrophages

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

Autophagy: A Player in response to Oxidative Stress and DNA Damage

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