Inhibition of thioredoxin-dependent H2O2 removal sensitizes malignant B-cells to pharmacological ascorbate

doi:10.1016/j.redox.2018.11.020

. 2019 Feb:21:101062.

doi: 10.1016/j.redox.2018.11.020. Epub 2018 Nov 29.

Inhibition of thioredoxin-dependent H₂O₂ removal sensitizes malignant B-cells to pharmacological ascorbate

Agnieszka Graczyk-Jarzynka¹, Agnieszka Goral², Angelika Muchowicz³, Radoslaw Zagozdzon⁴, Magdalena Winiarska⁵, Malgorzata Bajor⁶, Anna Trzeciecka⁷, Klaudyna Fidyt⁸, Joanna Alicja Krupka⁷, Julia Cyran⁹, Kacper Szczygiel⁷, Dimitar G Efremov¹⁰, Stefania Gobessi¹¹, Adam Jagielski¹², Karolina Siudakowska¹³, Malgorzata Bobrowicz¹⁴, Marta Klopotowska¹⁵, Joanna Barankiewicz¹⁶, Agata Malenda¹⁷, Ewa Lech-Maranda¹⁸, Nina Miazek-Zapala¹⁹, Piotr Henryk Skarzynski²⁰, Antoni Domagala⁷, Jakub Golab²¹, Malgorzata Firczuk²²

Affiliations

¹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
² Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
³ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
⁴ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka 59 Street, 02-006 Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5 A Street, 02-106 Warsaw, Poland. Electronic address: [email protected].
⁵ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
⁶ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
⁷ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland.
⁸ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Zwirki i Wigury 61 Street, 02-091 Warsaw, Poland. Electronic address: [email protected].
⁹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
¹⁰ Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Località Padriciano 99 Street, 34149 Trieste, Italy. Electronic address: [email protected].
¹¹ Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Località Padriciano 99 Street, 34149 Trieste, Italy.
¹² Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Miecznikowa 1 Street, 02-096 Warsaw, Poland.
¹³ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
¹⁴ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
¹⁵ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Zwirki i Wigury 61 Street, 02-091 Warsaw, Poland. Electronic address: [email protected].
¹⁶ Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland; Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medicine, Marymoncka 99/103 Street, 01-813 Warsaw, Poland.
¹⁷ Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland.
¹⁸ Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland; Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medicine, Marymoncka 99/103 Street, 01-813 Warsaw, Poland. Electronic address: [email protected].
¹⁹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Institute of Physiology and Pathology of Hearing, World Hearing Center, Mochnackiego 10 Street, 02-042 Warsaw, Poland.
²⁰ Institute of Physiology and Pathology of Hearing, World Hearing Center, Mochnackiego 10 Street, 02-042 Warsaw, Poland; Institute of Sensory Organs, Mokra 17 Street, 05-830 Kajetany, Poland; Department of Heart Failure and Cardiac Rehabilitation, Medical University of Warsaw, Kondratowicza 8 Street, 03-242 Warsaw, Poland.
²¹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Centre for Preclinical Research and Technology, Medical University of Warsaw, Zwirki I Wigury 81 Street, 02-091 Warsaw, Poland. Electronic address: [email protected].
²² Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].

PMID: 30576925
PMCID: PMC6302138
DOI: 10.1016/j.redox.2018.11.020

Inhibition of thioredoxin-dependent H₂O₂ removal sensitizes malignant B-cells to pharmacological ascorbate

Agnieszka Graczyk-Jarzynka et al. Redox Biol. 2019 Feb.

. 2019 Feb:21:101062.

doi: 10.1016/j.redox.2018.11.020. Epub 2018 Nov 29.

Authors

Affiliations

¹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
² Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
³ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
⁴ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka 59 Street, 02-006 Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5 A Street, 02-106 Warsaw, Poland. Electronic address: [email protected].
⁵ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
⁶ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
⁷ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland.
⁸ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Zwirki i Wigury 61 Street, 02-091 Warsaw, Poland. Electronic address: [email protected].
⁹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
¹⁰ Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Località Padriciano 99 Street, 34149 Trieste, Italy. Electronic address: [email protected].
¹¹ Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Località Padriciano 99 Street, 34149 Trieste, Italy.
¹² Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Miecznikowa 1 Street, 02-096 Warsaw, Poland.
¹³ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
¹⁴ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].
¹⁵ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Zwirki i Wigury 61 Street, 02-091 Warsaw, Poland. Electronic address: [email protected].
¹⁶ Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland; Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medicine, Marymoncka 99/103 Street, 01-813 Warsaw, Poland.
¹⁷ Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland.
¹⁸ Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland; Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medicine, Marymoncka 99/103 Street, 01-813 Warsaw, Poland. Electronic address: [email protected].
¹⁹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Institute of Physiology and Pathology of Hearing, World Hearing Center, Mochnackiego 10 Street, 02-042 Warsaw, Poland.
²⁰ Institute of Physiology and Pathology of Hearing, World Hearing Center, Mochnackiego 10 Street, 02-042 Warsaw, Poland; Institute of Sensory Organs, Mokra 17 Street, 05-830 Kajetany, Poland; Department of Heart Failure and Cardiac Rehabilitation, Medical University of Warsaw, Kondratowicza 8 Street, 03-242 Warsaw, Poland.
²¹ Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Centre for Preclinical Research and Technology, Medical University of Warsaw, Zwirki I Wigury 81 Street, 02-091 Warsaw, Poland. Electronic address: [email protected].
²² Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland. Electronic address: [email protected].

PMID: 30576925
PMCID: PMC6302138
DOI: 10.1016/j.redox.2018.11.020

Abstract

L-ascorbate (L-ASC) is a widely-known dietary nutrient which holds promising potential in cancer therapy when given parenterally at high doses. The anticancer effects of L-ASC involve its autoxidation and generation of H₂O₂, which is selectively toxic to malignant cells. Here we present that thioredoxin antioxidant system plays a key role in the scavenging of extracellularly-generated H₂O₂ in malignant B-cells. We show that inhibition of peroxiredoxin 1, the enzyme that removes H₂O₂ in a thioredoxin system-dependent manner, increases the sensitivity of malignant B-cells to L-ASC. Moreover, we demonstrate that auranofin (AUR), the inhibitor of the thioredoxin system that is used as an antirheumatic drug, diminishes the H₂O₂-scavenging capacity of malignant B-cells and potentiates pharmacological ascorbate anticancer activity in vitro and in vivo. The addition of AUR to L-ASC-treated cells triggers the accumulation of H₂O₂ in the cells, which results in iron-dependent cytotoxicity. Importantly, the synergistic effects are observed at as low as 200 µM L-ASC concentrations. In conclusion, we observed strong, synergistic, cancer-selective interaction between L-ASC and auranofin. Since both of these agents are available in clinical practice, our findings support further investigations of the efficacy of pharmacological ascorbate in combination with auranofin in preclinical and clinical settings.

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Figures

**Fig. 1**
Lack of PRDX1 sensitizes malignant B-cells to pharmacological ascorbate *in vitro* and *in vivo*. A. The mRNA levels of PRDX1 in normal (CD19⁺ cells from peripheral blood of healthy donors, n = 4) and malignant (primary CLL, n = 7) B-cells were assessed by qPCR, using RPL29 gene as a reference. The results are shown as means ± SD. Statistical significance was assessed using unpaired t-test with Welch's correction; ***p < 0.001. B. PRDX1 knockout (3 different clones: Raji-sgPRDX1 A, B, and C) or control (Raji-sgGFP) cells were incubated with L-ASC at indicated concentrations for 48 h. To assess viability, the cells were stained with propidium iodide (PI) and analyzed by flow cytometry (left panel). The results are presented as % of dead cells (PI-positive cells) and show means + SD, n ≥ 4. Statistical significance between control (sgGFP) and PRDX1 knockout clones for each L-ASC concentration was assessed using 1-way ANOVA with Dunnett's post-hoc test; **p < 0.01, ***p < 0.001. Western blot analysis of total protein lysates prepared from PRDX1 knockout and control Raji cells (right panel). C. BALB/c SCID mice were inoculated subcutaneously with Raji-sgPRDX1 (a mixture of clones B and C) and Raji-sgGFP cells. L-ASC was administered intraperitoneally at a dose of 4 g/kg, twice daily, for 10 days. The graphs represent results from two pooled experiments, the number of mice in each group was 10. Statistical significance of tumor growth (left panel) between the following groups: Raji-sgGFP and Raji-sgPRDX1, Raji-sgGFP+L-ASC and Raji-sgPRDX1+L-ASC, as well as Raji-sgPRDX1 and Raji-sgPRDX1+L-ASC was assessed using 2-way ANOVA; *p < 0.05, ****p < 0.0001. Statistical significance of mice survival (right panel) was determined using log-rank survival test; *p < 0.05.

**Fig. 2**
AUR, an inhibitor of TXNRD, selectively enhances pharmacological ascorbate activity against malignant B-cells. A. Primary human CLL cells grown in monoculture (n ≥ 15 patients, left panel) and in a co-culture with M2–10B4 stromal cells (n ≥ 12 patients, right panel) were incubated for 48 h with indicated concentrations of L-ASC, AUR, or their combination. The percentage of apoptotic cells (% of dead cells) was assessed by annexin V/propidium iodide (PI) staining. Means ± SEM are presented. Statistical significance was evaluated using 1-way ANOVA test with Tukey's correction in AUR only groups vs combinations; ***p < 0.001, ****p < 0.0001. B. Normal human peripheral blood B-cells (human CD19⁺) grown in monoculture (n ≥ 2 donors, left panel) and B-cells isolated from human tonsils and co-cultured with HT1080-CD40L cells (centroblasts culture, n = 2 donors, right panel) were incubated with indicated concentrations of L-ASC, AUR or their combination. After 48 h, the percentage of dead cells was assessed by annexin V/PI staining. Means ± SD are presented. C. Human BL cell line Raji and CLL cell lines (Mec-1 and CI) were incubated with L-ASC, AUR, or both at indicated concentrations. After 48 h cells were stained with PI and the percentage of PI-positive cells was assessed by flow cytometry. The results are shown as means of three independent experiments + SD.

**Fig. 3**
L-ASC and AUR combination triggers the intracellular accumulation of H₂O₂ and H₂O₂-dependent cell death. A. Cell-free culture medium supplemented with 200 µM L-ASC, 200 µM D-ascorbate (D-ASC) or 200 µM L-dehydroascorbate (L-DHA) alone or in combination with 0.5 µM AUR was incubated for indicated time-points. PY1 probe was added to the medium at 10 μM final concentration. The fluorescence was measured using the excitation wavelength 514 nm and emission wavelength 550 nm. The amount of generated H₂O₂ was normalized to control (DMSO). The representative result (out of two independent experiments) is shown as means ± SD (n = 4). Statistical significance was evaluated using 2-way ANOVA with Tukey's multiple comparisons test and is shown for control vs L-ASC, control vs D-ASC and L-ASC vs D-ASC groups only; **** p < 0.0001 (left panel). Raji cells were incubated with 200 µM L-ASC, 200 µM D-ASC or 200 µM L-DHA alone or in combination with 0.4 µM AUR for 48 h. Thereafter the cells were stained with PI and their viability was assessed by flow cytometry. The results are shown as a mean percentage of dead cells + SD from two independent experiments. Statistical significance was evaluated using 1-way ANOVA test with Tukey's correction in L-ASC, D-ASC and L-DHA only groups and the corresponding combinations, ****p < 0.0001 (middle panel). Raji cells were incubated with glucose oxidase (GOx) and AUR at indicated concentrations, alone or in combination. After 48 h, the cells were stained with PI and the percentage of dead cells was evaluated by flow cytometry. Results are shown as means of three independent experiments + SD. Statistical significance was evaluated using 1-way ANOVA test with Tukey's correction in GOx only groups and the corresponding combinations with AUR, ***p < 0.001, ****p < 0.0001 (right panel). B. Raji cells expressing HyPer3 were incubated with 200 µM L-ASC, 0.5 µM AUR, or the combination of both. Where indicated, catalase (CAT,100 µg/ml) was added 30 min prior to addition of L-ASC and AUR. The intensity of green fluorescence was assessed at indicated time points by flow cytometry. The results are presented as fold change over untreated controls, as means from two experiments ± SD, n = 4. Statistical significance in control vs L-ASC+AUR group only for each time point was assessed using 1-way ANOVA test with Dunnett's post-hoc test; ***p < 0.001 (left panel). Raji cells pre-stained with 1.5 µM CM-H₂-DCFDA were incubated with 200 µM L-ASC, 0.5 µM AUR, or their combination. The intensity of green fluorescence of all living cells, gated based on SSC and FSC parameters, was assessed by flow cytometry at indicated time points. CAT (100 µg/ml) was added 30 min prior to addition of L-ASC and AUR to the indicated groups. The results are presented as fold over untreated control. Means of three independent experiments ± SD are presented. Statistical significance between each experimental group and the DMSO-treated control for each time-point was assessed using 1-way ANOVA with Dunnett's post-hoc test; **p < 0.01, ***p < 0.001, ****p < 0.0001 (middle panel). The viability of Raji cells incubated 48 h with the combination of 200 µM L-ASC and 0.5 µM AUR ± 100 µg/ml CAT was assessed by flow cytometry after PI staining. Bars present means of two independent experiments + SD (right panel).

**Fig. 4**
L-ASC and AUR combination results in iron-mediated oxidative damage and cytotoxicity. A. Raji-HyPer3 cells were pre-loaded for 1 h with indicated concentrations of deferoxamine (DFO), washed extensively with PBS, and treated with 200 µM L-ASC and 0.5 µM AUR. To evaluate intracellular H₂O₂ levels, the intensity of HyPer3 was assessed at indicated time points by flow cytometry. Means ± SD from two experiments (n = 4) normalized to untreated control are shown for each time point. B. Raji cells were pre-loaded with DFO as described in A. and treated with 200 µM L-ASC and 0.5 µM AUR. The H2A.X phosphorylation, a marker of DNA damage, was assessed upon 6 h of the incubation. Bars are means from three experiments + SD. Statistical significance was evaluated using 1-way ANOVA test with Tukey's correction in DFO-containing groups and AUR+L-ASC without DFO; *p < 0.05 (left panel). Raji cells were pre-loaded with DFO as described in A. and treated with 200 µM L-ASC and 0.5 µM AUR. PI staining was used to assess % of dead cells after 48 h of incubation. Bars are means from two experiments + SD (right panel). Statistical significance was evaluated using 1-way ANOVA test with Tukey's correction in DFO-containing groups and AUR+L-ASC without DFO; ****p < 0.0001.

**Fig. 5**
Schematic representation of a possible mechanism by which AUR augments L-ASC cytotoxicity in Fe²⁺-dependent manner. In extracellular fluid, L-ASC, in the presence of transition metal ions, generates H₂O₂, which enters the cell. In the absence of AUR, L-ASC is effectively removed by the TXN system, no oxidative damage occurs, and the cell survives (left panel). When the TXN system is blocked by AUR, H₂O₂ accumulates in the cell and, in the presence of Fe²⁺, generates highly reactive hydroxyl radicals, which lead to oxidative damage and cell death (middle panel). DFO chelates intracellular Fe²⁺, which impairs hydroxyl radical generation, relieves oxidative damage and results in partial cell survival (right panel).

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References

1. German Nutrition Society New reference values for vitamin C intake. Ann. Nutr. Metab. 2015;67(1):13–20. - PubMed
1. Chen Q. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. USA. 2007;104(21):8749–8754. - PMC - PubMed
1. Chen Q. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. USA. 2008;105(32):11105–11109. - PMC - PubMed
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[1] German Nutrition Society New reference values for vitamin C intake. Ann. Nutr. Metab. 2015;67(1):13–20. - PubMed

[2] German Nutrition Society New reference values for vitamin C intake. Ann. Nutr. Metab. 2015;67(1):13–20. - PubMed

[3] Chen Q. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. USA. 2007;104(21):8749–8754. - PMC - PubMed

[4] Chen Q. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. USA. 2007;104(21):8749–8754. - PMC - PubMed

[5] Chen Q. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. USA. 2008;105(32):11105–11109. - PMC - PubMed

[6] Chen Q. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. USA. 2008;105(32):11105–11109. - PMC - PubMed

[7] Levine M., Padayatty S.J., Espey M.G. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv. Nutr. 2011;2(2):78–88. - PMC - PubMed

[8] Levine M., Padayatty S.J., Espey M.G. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv. Nutr. 2011;2(2):78–88. - PMC - PubMed

[9] Kawada H. Phase I clinical trial of intravenous L-ascorbic acid following salvage chemotherapy for relapsed B-cell non-hodgkin's lymphoma. Tokai J. Exp. Clin. Med. 2014;39(3):111–115. - PubMed

[10] Kawada H. Phase I clinical trial of intravenous L-ascorbic acid following salvage chemotherapy for relapsed B-cell non-hodgkin's lymphoma. Tokai J. Exp. Clin. Med. 2014;39(3):111–115. - PubMed

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Inhibition of thioredoxin-dependent H₂O₂ removal sensitizes malignant B-cells to pharmacological ascorbate

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Inhibition of thioredoxin-dependent H₂O₂ removal sensitizes malignant B-cells to pharmacological ascorbate

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