Role of labile iron in the toxicity of pharmacological ascorbate

Du, Juan; Wagner, Brett A.; Buettner, Garry R.; Cullen, Joseph J.

doi:10.1016/j.freeradbiomed.2015.03.033

Cited by 60 publications

(56 citation statements)

References 48 publications

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“…As both H 2 O 2 toxicity and ascorbate oxidation to generate H 2 O 2 are dependent upon metal ion redox chemistry (Buettner and Jurkiewicz, 1996; Du et al, 2015a; Halliwell and Gutteridge, 1990), it follows that ascorbate toxicity may be dependent on intracellular pro-oxidant metal ion chemistry, as has previously been suggested in breast and prostate cancer (Verrax and Calderon, 2009). Indeed, chelators that inhibit redox cycling of iron (desferrioxamine, DFO; diethylenetriamine-pentaacetic acid, DTPA) (Buettner, 1986) significantly inhibited ascorbate toxicity in both NSCLC and GBM cell lines (Figure 4D; Figures S2B, S2C).…”

Section: Resultsmentioning

confidence: 78%

O 2 ⋅− and H 2 O 2 -Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

et al. 2017

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Summary Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2•− and H2O2 are capable of disrupting intracellular iron metabolism thereby selectively sensitizing non-small cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

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Section: Resultsmentioning

confidence: 78%

O 2 ⋅− and H 2 O 2 -Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

et al. 2017

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“…However, many other factors can modulate the toxicity of P-AscH − , e.g. KRAS status [3], the level of catalytic metals [60], [61], the redox status of the intracellular GSSG,2 H + /2GSH redox couple [45], [62], and the status of NAD [58]. Yun et al recently extended the observations that ascorbate selectively kills KRAS and BRAF mutant cells [59]; they suggest that P-AscH − has as a target the redox state of GAPDH.…”

Section: Discussionmentioning

confidence: 99%

Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy

et al. 2016

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Ascorbate (AscH−) functions as a versatile reducing agent. At pharmacological doses (P-AscH−; [plasma AscH−] ≥≈20 mM), achievable through intravenous delivery, oxidation of P-AscH− can produce a high flux of H2O2 in tumors. Catalase is the major enzyme for detoxifying high concentrations of H2O2. We hypothesize that sensitivity of tumor cells to P-AscH− compared to normal cells is due to their lower capacity to metabolize H2O2. Rate constants for removal of H2O2 (kcell) and catalase activities were determined for 15 tumor and 10 normal cell lines of various tissue types. A differential in the capacity of cells to remove H2O2 was revealed, with the average kcell for normal cells being twice that of tumor cells. The ED50 (50% clonogenic survival) of P-AscH− correlated directly with kcell and catalase activity. Catalase activity could present a promising indicator of which tumors may respond to P-AscH−.

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“…The chelation of intracellular labile iron by PG SK quenches its fluorescence. The presence of effective iron-chelating agents leads to the removal of iron from the PG SK-iron complex, and the de-quenching of PG SK fluorescence [24,25]. …”

Section: Methodsmentioning

confidence: 99%

Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells

Andrés

Commissariat

Dunn

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Salicylaldehyde isonicotinoyl hydrazone (SIH) is an iron chelator of the aroylhydrazone class that displays antioxidant or prooxidant effects in different mammalian cell lines. Because the liver is the major site of iron storage, elucidating the effect of SIH on hepatic oxidative metabolism is critical for designing effective hepatic antioxidant therapies. Methods Hepatocyte-like HepG2 cells were exposed to SIH or to analogs showing greater stability, such as N′-[1-(2-Hydroxyphenyl)ethyliden]isonicotinoyl hydrazide (HAPI), or devoid of iron chelating properties, such as benzaldehyde isonicotinoyl hydrazone (BIH), and toxicity, oxidative stress and antioxidant (glutathione) metabolism were evaluated. Results Autoxidation of Fe2+ in vitro increased in the presence of SIH or HAPI (but not BIH), an effect partially blocked by Fe2+ chelation. Incubation of HepG2 cells with SIH or HAPI (but not BIH) was non-toxic and increased reactive oxygen species (ROS) levels, activated the transcription factor Nrf2, induced the catalytic subunit of γ-glutamate cysteine ligase (Gclc), and increased glutathione concentration. Fe2+ chelation decreased ROS and inhibited Nrf2 activation, and Nrf2 knock-down inhibited the induction of Gclc in the presence of HAPI. Inhibition of γ-glutamate cysteine ligase enzymatic activity inhibited the increase in glutathione caused by HAPI, and increased oxidative stress. Conclusions SIH iron chelators display both prooxidant (increasing the autoxidation rate of Fe2+) and antioxidant (activating Nrf2 signaling) effects. General significance Activation by SIH iron chelators of a hormetic antioxidant response contributes to its antioxidant properties and modulates the anti- and pro-oxidant balance.

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Role of labile iron in the toxicity of pharmacological ascorbate

Cited by 60 publications

References 48 publications

O 2 ⋅− and H 2 O 2 -Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

O 2 ⋅− and H 2 O 2 -Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy

Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells

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