O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Schoenfeld, Joshua D.; Sibenaller, Zita A.; Mapuskar, Kranti A.; Wagner, Brett A.; Cramer-Morales, Kimberly; Furqan, Muhammad; Sandhu, Sonia; Carlisle, Thomas; Smith, Mark C.; Hejleh, Taher Abu; Berg, Daniel J.; Zhang, Jun; Keech, John; Parekh, Kalpaj R.; Bhatia, Sudershan K.; Monga, Varun; Bodeker, Kellie L.; Ahmann, Logan; Vollstedt, Sandy; Brown, Heather A.; Kauffman, Erin P. Shanahan; Schall, Mary E.; Hohl, R. J.; Clamon, Gerald H.; Greenlee, Jeremy D.W.; Howard, Matthew A.; Schultz, Michael K.; Smith, Brian J.; Riley, Dennis P.; Domann, Frederick E.; Cullen, Joseph J.; Buettner, Garry R.; Buatti, John M.; Spitz, Douglas R.; Allen, Bryan G.

doi:10.1016/j.ccell.2017.07.008

Cited by 120 publications

(159 citation statements)

References 70 publications

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“…1A, B). These data confirmed conclusions from previous studies that pharmacological concentrations of ascorbate selectively induced cell death in cancer cells versus normal cells, through formation of H 2 O 2 (12,20,21,33). A previous study suggested that ascorbate induced cancer cell cytotoxicity by enhanced cellular uptake via its oxidized form dehydroascorbate (DHA) (32), however the study did not report data with direct DHA treatment on cancer cells.…”

Section: Resultssupporting

confidence: 91%

Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis

Chen

Wilkins

et al. 2017

Free Radical Biology and Medicine

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An ascorbate-mediated production of oxidative stress has been shown to retard tumor growth. Subsequent glycolysis inhibition has been suggested. Here, we further define the mechanisms relevant to this observation. Ascorbate was cytotoxic to human neuroblastoma cells through the production of H2O2, which led to ATP depletion, inhibited GAPDH, and non-apoptotic and non-autophagic cell death. The mechanism of cytotoxicity is different when PARP-dependent DNA repair machinery is active or inhibited. Ascorbate-generated H2O2 damaged DNA, activated PARP, depleted NAD+, and reduced glycolysis flux. NAD+ supplementation prevented ATP depletion and cell death, while treatment with a PARP inhibitor, olaparib, preserved NAD+ and ATP levels but led to increased DNA double-strand breakage and did not prevent ascorbate-induced cell death. These data indicate that in cells with an intact PARP-associated DNA repair system, ascorbate-induced cell death is caused by NAD+ and ATP depletion, while in the absence of PARP activation ascorbate-induced cell death still occurs but is a consequence of ROS-induced DNA damage. In a mouse xenograft model, intraperitoneal ascorbate inhibited neuroblastoma tumor growth and prolonged survival. Collectively, these data suggest that ascorbate could be effective in the treatment of glycolysis-dependent tumors. Also, in cancers that use alternative energy metabolism pathways, combining a PARP inhibitor with ascorbate treatment could be useful.

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Section: Resultssupporting

confidence: 91%

Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis

Chen

Wilkins

et al. 2017

Free Radical Biology and Medicine

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“…To further confirm labile Fe plays a key role in the cytotoxic effect observed with DPEN + CuSO 4 , intracellular LIPs were measured in H292 lung cancer cells and normal lung epithelial cells HBEpC using Calcein-AM as previously described [30] (Figure 4D). This probe binds Fe(II) rapidly, stoichiometrically, and reversibly while forming fluorescence-quenched Calcein-Fe complexes.…”

Section: Resultsmentioning

confidence: 99%

“…Others have demonstrated that H 2 O 2 , generated via plasma activated media, induces apoptosis in lung cancer cells compared to normal cells in a Fe(II) dependent mechanism [39]. Based on alterations in oxidative metabolism as well as differences in redox active metal ions in cancer cells, agents that generate H 2 O 2 represent new therapeutic tools for selectively killing cancer [25, 30]. …”

Section: Discussionmentioning

confidence: 99%

D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H 2 O 2 -mediated oxidative stress

Sciegienka

Solst

Falls

et al. 2017

Free Radical Biology and Medicine

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D-penicillamine (DPEN), a copper chelator, has been used in the treatment of Wilson's disease, cystinuria, and rheumatoid arthritis. Recent evidence suggests that DPEN in combination with biologically relevant copper (Cu) concentrations generates H2O2 in cancer cell cultures, but the effects of this on cancer cell responses to ionizing radiation and chemotherapy are unknown. Increased steady-state levels of H2O2 were detected in MB231 breast and H1299 lung cancer cells following treatment with DPEN (100 μM) and copper sulfate (15 μM). Clonogenic survival demonstrated that DPEN-induced cancer cell toxicity was dependent on Cu and was significantly enhanced by depletion of glutathione [using buthionine sulfoximine (BSO)] as well as inhibition of thioredoxin reductase [using Auranofin (Au)] prior to exposure. Treatment with catalase inhibited DPEN toxicity confirming H2O2 as the toxic species. Furthermore, pretreating cancer cells with iron sucrose enhanced DPEN toxicity while treating with deferoxamine, an Fe chelator that inhibits redox cycling, inhibited DPEN toxicity. Importantly, DPEN also demonstrated selective toxicity in human breast and lung cancer cells, relative to normal untransformed human lung or mammary epithelial cells and enhanced cancer cell killing when combined with ionizing radiation or carboplatin. Consistent with the selective cancer cell toxicity, normal untransformed human lung epithelial cells had significantly lower labile iron pools than lung cancer cells. These results support the hypothesis that DPEN mediates selective cancer cell killing as well as radio-chemo-sensitization by a mechanism involving metal ion catalyzed H2O2-mediated oxidative stress and suggest that DPEN could be repurposed as an adjuvant in conventional cancer therapy.

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“…Vitamin C also participates indirectly as an antioxidant by regenerating vitamin E, contributing to antioxidant protection against lipid peroxidation and in the elimination of free radicals (Jiang 2014, Traber 2007. Nevertheless, in presence of transition metals (Schoenfeld et al 2017) or under decreased levels of glutathione (Nauser et al 2015), ascorbic acid can behave as an oxidative molecule, increasing the production of oxygen free radicals. This property has been recently explored to kill cancer cells (Schoenfeld et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, in presence of transition metals (Schoenfeld et al 2017) or under decreased levels of glutathione (Nauser et al 2015), ascorbic acid can behave as an oxidative molecule, increasing the production of oxygen free radicals. This property has been recently explored to kill cancer cells (Schoenfeld et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Effects of ascorbic acid on anxiety state and affect in a non-clinical sample

Moritz

Schwarzbold

Guarnieri

et al. 2017

Acta Neurobiologiae Experimentalis

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Objective Given that the literature data indicates that ascorbic acid may have an anxiolytic effect, we hypothesized that a single oral administration of ascorbic acid could acutely affect emotional states. Methods The effects of acid ascorbic supplementation on anxiety and other emotional states were evaluated by the State-Trait Anxiety Inventory (STAI), and Visual Analogue Mood Scale (VAMS). Immediately before, and 2 hours after receiving a single ascorbic acid dose (1000 mg) or placebo, 142 graduate students were evaluated by the STAI and VAMS in a randomized, double-blind, placebo-controlled trial. Results No changes from basal levels were observed in the STAI state-anxiety or VAMS scores. However, the ingestion of ascorbic acid by the 25% more anxious healthy subjects (women; 14 control and 23 ascorbic acid), as defined by the STAI trait-anxiety scale, produced a significant reduction from baseline anxiety scores in the STAI state-anxiety scale and VAMS anxiety subscale. The study evaluated a small sample with narrow sociodemographic characteristics, composed mainly of healthy young females (> 94%) enrolled in post-graduation courses, without controlling diet, physical activity, and formal psychiatric diagnosis. Conclusions: Despite the sample size limitation, this study provides the first evidence of an acute anxiolytic effect of ascorbic acid. Broader population studies are required to evaluate the clinical relevance of presented data.

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O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Cited by 120 publications

References 70 publications

Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis

Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis

D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H 2 O 2 -mediated oxidative stress

Effects of ascorbic acid on anxiety state and affect in a non-clinical sample

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