Pro-oxidant effects of ascorbate

 

Ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide (H2O2). In the presence of catalytic metals this oxidation is accelerated.

 

Recent pharmacokinetic data indicate that intravenous (i.v.) administration of ascorbate bypasses the tight control of the gut producing highly elevated plasma levels; ascorbate at very high levels can act as prodrug to deliver a significant flux of H2O2 to tumors.

 

In the presence of catalytic metal ions, ascorbate can also exert pro-oxidant effects [14,128,129]. Ascorbate is an excellent one-electron reducing agent that can reduce ferric (Fe3+) to ferrous (Fe2+) iron, while being oxidized to ascorbate radical (Reaction 6). Depending on co-ordination environment, Fe2+ can readily react with O2, reducing it to superoxide radical (Reaction 7), which in turn dismutes to H2O2 and O2 (Reaction 8).

 

AscH- + Fe3+ Asc•- + Fe2+  (6)

Fe2++O2Fe3++O∙−2

(7)

O∙−2+O∙−2+2H+H2O2+O2.

(8)

In a classic Fenton reaction, Fe2+ reacts with H2O2 to generate Fe3+ and the very oxidizing hydroxyl radical, Reaction 9. The presence of ascorbate can allow the recycling of Fe3+ back to Fe2+, which in turn will catalyze the formation of highly reactive oxidants from H2O2.

 

Fe2+ + H2O2 Fe3+ + HO•(Fenton reaction).      (9)

Depending on concentrations, the effects of ascorbate on models of lipid peroxidation can be pro- or antioxidant [14,130]. There is considerable variability in the literature; this variability appears to be a result of the different concentrations and form of transition metal ions in the experiments and the media [131].

 

The prooxidant effects of ascorbate may be important in vivo depending on the availability of catalytic metal ions. In healthy individuals, iron is largely sequestered by iron binding proteins such as transferrin and ferritin [132,133]. Transferrin is a glycoprotein that is synthesized in the liver. It is the major circulating iron binding protein with a high affinity, but low capacity for iron; this iron is essentially redox inactive [134]. Transferrin avidly binds to the transferrin receptor on the cell surface. The transferrinCtransferrin receptor complex is internalized to an endosome, which releases iron in acidic conditions. The ferric iron released is reduced and transported to the cytoplasm where it is either utilized for synthesis of iron-containing proteins or bound in ferritin, an iron storage protein. Ferritin is capable of sequestering up to 4500 atoms of iron, but is normally only 20% saturated. Iron stored in ferritin can be released by appropriate reductants in the presence of a chelator or by degradation of ferritin in the lysosome.

 

Iron can be released from ferritin by biological reductants such as thiols, ascorbate and reduced flavins [135]. The released iron enables cells to synthesize cytochromes and iron-containing enzymes. However, uncontrolled release of iron from ferritin has the potential to form HO•, which can damage critical cellular components [136C138].

 

In pathological situations, such as thalassaemia or hemotochromatosis, non-transferrin-bound iron is present. Thus, supplemental ascorbate without administration of an iron chelator can lead to deleterious effects [14]. Tissue damage resulting from ischemia/reperfusion is another example of increased availability of catalytic metal occurring in vivo [139]. Intravenous ascorbate prior to vascular surgery increased concentrations of ascorbate radical and lipid hydroperoxides suggesting that catalytic iron released into the circulation during the ischemic phase of the surgery with ascorbate may promote iron-induced lipid peroxidation [140,141].

 

Elevated levels of catalytic metal ions have also been demonstrated in chronic inflammatory diseases [142]. There is an increased deposition of iron proteins in the synovial membranes in rheumatoid arthritis. Ascorbate radical has been detected in synovial fluid from patients with synovitis disease indicating that catalytic iron is in part responsible for the decreased levels of ascorbate and increased levels of DHA [141]. In addition, ascorbate concentrations were decreased while levels of catalytic iron increased in patients with sepsis, compared to healthy subjects [143].

 

Although there is no direct evidence that catalytic iron is increased in tumors, many patients with malignant disease have elevated serum or tissue ferritin concentrations [144C146]. Raised levels of circulating ferritin are found in childhood Hodgkins lymphoma and are associated with poor survival [147]; serum ferritin levels have been shown to be related to the stage of the disease and tumor volume in cervical cancer [148]. Furthermore, studies by Feng et al. [149] have shown that the peritoneal and subcutaneous microvessels of normal mice were largely impermeable to circulating ferritin, but in mice bearing solid or ascites tumors, circulating ferritin was found in the basal lamina and extravascular space, suggesting that tumor vessels are hyperpermeable to circulating macromolecules such as ferritin. In fact, ferritin staining was detected in stroma and histiocytes surrounding neoplastic cells of breast carcinoma tissue of patients [150]. Extracellular metal-containing proteins have been proposed to be essential for the pro-oxidant effects of ascorbate [10,129], iron-saturated ferritin could be a potential candidate as source of catalytic iron. A recent study by Deubzer et al. [151] demonstrated that ferritin released by neuroblastoma cells enhanced pharmacologic ascorbate induced-cytotoxicity, indicating that ferritin with high iron-saturation could be a source of catalytic iron [152]. Consistent with this, ascorbate has also been shown to be capable of releasing iron from cellular ferritin [158]. Ferritin is only one candidate as a source of catalytic iron; extracellular iron chelates are present in tissue and seem to be increased under pathological conditions [159]. It is clear that only low levels of catalytic metals are needed to substantially increase the rate of oxidation of ascorbate [15,18]. These many observations provide insights on the mechanism by which pharmacologic concentrations of ascorbate have potential in treating certain types of cancer.

 

8. Ascorbate and cancer treatment

The use of high-dose ascorbate in treating cancer patients began in the 1970s. These early studies demonstrated beneficial effects of high-dose ascorbate [155C158]. However, two double-blinded, randomized clinical trials at the Mayo Clinic did not show any benefit [169,160]. Subsequently, use of ascorbate for cancer treatment was considered ineffective and dismissed by the research and medical communities. However, a marked difference existed in these studies. Camerons group gave patients ascorbate intravenously as well as orally, while patients in the Mayo Clinic trials received only oral ascorbate. Some years later, clinical data were generated that demonstrated that when ascorbate is given orally, plasma concentrations are tightly controlled [101]. At oral doses of 200 mg, the steady-state plasma concentrations are 80 M. As doses exceed 200 mg, relative absorption decreases, urine excretion increases and the fraction of bioavailable ascorbate is reduced [7]. Peak plasma values do not exceed 220 M even after maximum oral dose of 3 g 6 times daily [8]. In contrast, when ascorbate is administered intravenously, millimolar concentrations can be achieved. In fact, infusion of 10 g of ascorbate in cancer patients results in plasma concentrations of 1 to 5 mM [161,162]. Thus, only intravenous administration of ascorbate can yield high plasma levels, i.e. pharmacological levels.

 

8.1. The role of hydrogen peroxide generation and removal

 

In vitro, the toxicity of ascorbate centers on the generation of H2O2 by ascorbate upon its oxidation [9,10,12,163,164]. The true autoxidation of ascorbate, i.e. in the absence of catalytic metals, via reaction 2 will generate considerable amounts of H2O2 when ascorbate is at millimolar levels. For example, in an aqueous solution containing 20 mM ascorbate at pH 7.4, the concentration of ascorbate dianion, Asc2, will be on the order of 1 M. This will result in a flux of H2O2 on the order of 10 nM s1, in a typical cell culture experiment.

 

Catalytic iron (and perhaps copper) in the media and serum will increase the rate of ascorbate oxidation and associated generation of H2O2. Clement et al. found that Dulbeccos modification of Eagles MEM (DMEM) generates more H2O2 than RPMI 1640 during a 6-hour incubation with increasing concentrations of ascorbate [165]. In addition to adventitious iron, DMEM has 0.25 M Fe (NO3)3 in its formulation, which could contribute to this greater production of H2O2 in DMEM than that from RPMI. Serum usually contains total iron at a range of 10 to 50 M, which could also be another factor that causes the variable toxicity of ascorbate in different media; however, some of this iron will be redox inactive as it will be sequestered in transferrin [134]; there will undoubtedly be a highly variable amount of iron present that has nonspecific peroxidase activity [166]. This iron will actively catalyze the oxidation of ascorbate. Thus, the amount of catalytic iron present in typical cell culture media is highly variable. Even with careful attention to detail, this can lead to considerable variability in experimental results, even in the same set of experiments.

 

-Keto acids such as pyruvate and -ketoglutarate directly react with H2O2 when present in cell culture media [172];

 

CH3( = O)( = O)OH + H2O2 CH3C( = O)OH + CO2   (10)

this will result in an apparent lowering of the toxicity of ascorbate [168]. Thus, the presence of -keto acids in media must be taken into consideration in the design and interpretation of data from experiments where the oxidation of ascorbate and associated production of H2O2 are central to the study.

 

Because cells rapidly and efficiently remove extracellular H2O2, observed toxicities or cell killing induced by ascorbate is an inverse function of cell density [151,153,169]. There is an array of intracellular antioxidant enzymes involved in the removal of H2O2, such as catalase, glutathione peroxidase, and the peroxiredoxins. Although modest catalase activity has been detected in heart mitochondria [170], catalase is predominantly located in peroxisomes of mammalian cells. Concomitant administration of the catalase inhibitor amino-1,2,4-triazole has been shown to enhance ascorbate toxicity to Ehrlich ascites cells in vitro [171]. Using adenovirus constructs containing human catalase cDNA, Du et al. [12] demonstrated that overexpressing intracellular catalase protected cells from ascorbate-induced cytotoxicity. These results provide evidence supporting a fundamental role for H2O2 in ascorbate-induced toxicity.

 

Cytosolic glutathione peroxidase (GPx1), another antioxidant enzyme that removes peroxide, is widely distributed in tissues. GPx1 catalyzes GSH-dependent reduction of H2O2 to water. Gaetani et al. [172,173] have shown that the intracellular concentration of H2O2 in human erythrocytes is inversely proportional to the activity of catalase and GPx-1. GPx1 is responsible for eliminating low concentrations of H2O2; however, at high fluxes of H2O2 recycling of GPx1 by GSH becomes rate-limiting [174]; at high fluxes of H2O2 catalase is the enzyme that is principally responsible for removal of H2O2 [175].

 

Another antioxidant system that contributes to removal of H2O2 within cells is the family of peroxiredoxins, in particular, peroxiredoxin 2 (Prx2). Prx2 is the third most abundant protein in erythrocytes [176]. The rate constant of human Prx2 reacting with H2O2 is 1.3107 M1 s1 [177] which is similar to that of catalase (1.7 107 M1 s1 [178]). These complementary enzymes systems for the removal of intracellular H2O2 in RBCs will also make these cells efficient sinks for H2O2.

 

8.2. Ascorbate-induced cytotoxicity in vitro

 

Chen et al. [9,11] have demonstrated that some cancer cells have increased sensitivity to ascorbate-induced cytotoxicity compared to normal cells. In a complementary study, Du et al. [12] demonstrated that pancreatic cancer cells are more sensitive to pharmacological concentrations of ascorbate than their normal cell counterparts. The difference in sensitivity between normal and cancer cells towards ascorbate may be due to low levels of antioxidant enzymes and high endogenous levels of ROS in cancer cells [179C181]. The relative lower activities of catalase, glutathione peroxidase, and peroxiredoxins in cancer cells could potentially contribute to less efficient removal of H2O2 and increased sensitivity to ascorbate-induced cytotoxicity.

 

The rate of oxidation of ascorbate is typically a function of the level of catalytically active iron and copper in solution. Iron in cell culture media contributes significantly to the rate of H2O2 generation. Deferoxamine (Desferal® or DFO) is an iron-chelating agent that renders iron catalytically inactive with respect to ascorbate oxidation [15]. Although hydrophilic, DFO is cell-permeable; short-term exposure to DFO is not effective in accessing cytosolic labile iron pool (LIP) of cells from different origins [182]. However, short-term pre-incubation of cells to DFO appeared to protect cells from ascorbate-induced toxicity [184]. These observations indicate that DFO either is effective in accessing endosomal iron [182] or iron associated with cellular membranes [183]. Other cell culture studies have demonstrated that Fe2+ in the media can actually protect cells from the oxidative damage resulting from exposure to extracellular H2O2 [184,185]. Although hydroxyl radicals are produced via the Fenton reaction, most will not induce cell damage, but rather disappear by reactions with components of the media. The key is that H2O2 is removed. Thus, interpretation of data from experiments with iron, ascorbate, H2O2 or some combination is not always straightforward.

 

Oxidative stress has been shown to increase the levels of catalytic iron in tissues. A series of electron paramagnetic resonance (EPR) studies demonstrated that ultraviolet light increased the levels of labile iron in skin [186]; heat stress-induced oxidative events increased the level of labile iron in liver [187]; and ischemia reperfusion increased the level of catalytic iron in the heart [188]. In addition, ionizing radiation and some chemotherapeutic drugs have been shown to increase catalytic free iron levels [189C191]. Since it takes only very low concentrations of catalytic metals to bring about the rapid oxidation of ascorbate [192,193], approaches that increase catalytic iron could potentially enhance the cytotoxicity of pharmacologic ascorbate in vivo [194].

 

Porphyrin-based SOD mimics have a redox-active metal (Mn, Fe, and Cu) center and a stable porphyrin complex. The dismutation of O2 • by Mn porphyrin complexes involves two steps in which the Mn center cycles between Mn(III) and Mn(II): the first step is the reduction of Mn(III) by O2 • to yield Mn(II) and O2 and the second step the oxidation of Mn(II) by O2 to yield H2O2 and return the manganese to its resting state as Mn(III) porphyrin [195]. However, in the presence of a reductant such as ascorbate, Mn porphyrins function as superoxide reductases rather than dismutases; Mn(III) can be reduced to Mn(II) by ascorbate while Mn(II) can react with O2 forming O2 • , which subsequently forms H2O2 and O2, Reaction 8. The prooxidant effects of Mn porphyrin and ascorbate have been studied by several groups. Gardner et al. [196] have demonstrated that MnTM-4-PyP5+ catalyzes the oxidation of ascorbate in vitro. Zhong et al. [197] have shown synergistic killing of human prostate cancer cell RWPE-2 by MnTM-4-PyP5+ and ascorbate. Most recently, Tian et al. [198] have shown that MnTM-4-PyP5+ synergizes with ascorbate inhibiting the growth of prostatic, pancreatic, and hepatic cancer cells. Furthermore, the cytotoxic effects of two Mn(III) alkylpyridylporphyrins (MnTE-2-PyP5+ and MnTnHex-2-PyP5+) and ascorbate have been demonstrated in Caco-2, HeLa, HCT116, and 4T1 cells [199,200]. The more lipophilic MnTnHex-2-PyP5+ appeared much more effective. Given that several Mn porphyrins have already been tested in vivo as SOD mimetics, and by themselves have shown low toxicities at micromolar levels [195], there is great potential for using Mn porphyrins as an adjuvant to enhance the efficacy of pharmacologic ascorbate.

 

8.3. High dose ascorbate in animal studies

 

As mentioned above, the uptake of oral ascorbate in humans is tightly controlled by the gut and kidney filtration [7]. Rats receiving ascorbate by gavage (0.5 mg g1) increased blood and extracellular concentration to peak levels <150 M [10]. By contrast, concentrations reached peak levels of nearly 3 mM in rats receiving intraperitoneal injections, while intravenous injection increased peak levels to >8 mM. In a similar study, mice receiving bolus intravenous injections of ascorbate (1 g kg1), resulted in plasma concentrations of 15 mM [164]. Supplementation of ascorbate in drinking water at 1 g kg1 only increased plasma concentrations to <50 M. These results clearly indicate that pharmacologic concentrations of ascorbate cannot be obtained by oral administration.

 

In addition to the finding that millimolar levels of ascorbate were achieved by parenteral administration, Chen and colleagues [10] demonstrated that ascorbate radical was formed in extracellular fluid but was not detectable in whole blood. Moreover, H2O2 was detected in extracellular fluid, but not in the blood; H2O2 correlated with ascorbate radical concentration. These results indicate that plasma membrane associated ascorbate radical reductase and high levels of catalase, glutathione peroxidase, and peroxiredoxin enable erythrocytes to act as a sink for extracellular ascorbate radical and H2O2 [176,107]. On the other hand, ascorbate could be oxidized by catalytic iron associated with damaged proteins in the extracellular space [201C203, 209]. Considering that the permeability of tumor vessels is much higher compared to normal endothelium, tumor endothelium may permit the outflow of macromolecules, such as albumin, to interstitial fluid [169,204]. The fluid that accumulated in the peritoneal cavities of ascites tumor-bearing mice had a protein concentration several-fold greater than that of normal peritoneal fluid, with approximately 85% of the protein level of plasma, including albumin, in a proportion similar to that found in plasma [205,206]. Human albumin is the most abundant protein in the plasma; and has the capacity to bind to metal ions such as Cu2+ [207]. The first four amino acids of the N-terminus of human albumin Asp-Ala-His-Lys forms a tight-binding site for Cu2+ [207]. In fact, almost thirty years ago, Linus Pauling and his colleagues [194] designed a copper:glycylglycylhistidine complex that mimics the binding of albumin to copper; it enhanced the antitumor activity of ascorbate against Ehrlich ascites tumor cells. In addition, extracellular fluids contain little or no catalase activity, and low levels of SOD and GPx [208]. Thus, the H2O2 generated by ascorbate oxidation in the extracellular space could accumulate to a concentration greater than the intracellular level resulting in net rate of diffusion across the cell membrane into cells, resulting in toxicity to cancer cells [10].

 

Pharmacological ascorbate inhibits tumor growth in mice. In mice bearing tumor xenografts of pancreatic cancer, treatment with 4 g kg1 ascorbate (i.p., twice daily) significantly decreased the rate of tumor growth [11,12,164] (Table 4). Upon cessation of treatment with pharmacological ascorbate, the rate of tumor growth increased. This rate was similar to the rate observed in the control group, i.e. no ascorbate (Du et al., unpublished results). In this tumor model pharmacologic ascorbate as a single agent was cytostatic, not cytotoxic. Obviously, the use of intravenous high dose ascorbate as a single agent for cancer was not curative. To test the combination effect of standard chemotherapy with ascorbate, Espey et al. [209] have shown that synergistic cytotoxic effects can be achieved with gemcitabine and ascorbate in pancreatic cancer both in vitro and in a nude-mouse model. These data provide support for investigating the use of pharmacologic ascorbate as an adjuvant for conventional cancer chemotherapies.

 

Table 4

 

Pro-oxidant effects of ascorbate in animal models.

 

Species   Cell type Treatment     Effects    Ref

Balb/c nude mice  HT29 colon cancer       Asc 15 mg, 100, 1000 mg/kg, i.p., daily. 4 weeks.      7/7 mice survived at 1000 mg/kg. No carcinogenic invasion. Tumor volumes decrease. ARSs and EiFs genes down regulated.  [262]

Balb/c nude mice  K562 leukemia      Vit K3 10 mg/kg, i.p.; Asc 1 g/kg, i.p.       Asc+vit K3 decrease tumor growth.   [263]

Ncr nude mice      Ovcar5 ovarian cancer Asc 4 g/kg, i.p., twice daily. 30 days.       No adverse effects. Decrease tumor growth.    [11]

Ncr nude mice      Pan02 pancreatic cancer     Asc 4 g/kg, i.p., daily. 14 days.       No adverse effects. Decrease tumor growth.    [11]

Ncr nude mice      9 L rat glioblastoma     Asc 4 g/kg, i.p., twice daily. 12 days.       No adverse effects. Decrease tumor growth.

Prevent metastases.     [11]

Ncr nude mice      Pan02 pancreatic cancer     Asc 4 g/kg, i.p., daily; Gemcitabine 30, 60 mg/kg, i.p., every 4 days. 21 days.    No side effects except osmotic stress.

Asc+Gem significantly decrease tumor growth.       [209]

Ncr nude mice      PANC-1 pancreatic cancer  Asc 4 g/kg, i.p., daily; Gemcitabine 30, 60 mg/kg, every 4 days. 33 days.   No side effects except osmotic stress.

Asc+Gem significantly decrease tumor growth.       [209]

Nude mice    MIA PaCa-2 pancreatic cancer   Asc 4 g/kg, i.p., twice daily. 14 days.      No adverse effects. Decrease tumor growth.    [12]

NMRI mice    TLT Murine hepatoma  Asc 1 g/kg, i.p., daily. 30 days.       Decrease tumor growth.      [164]

Nude mice    H322 non-small cell lung cancer Asc 250 mg/kg, i.p.; 101 F6 nanoparticle i.v.    Asc synergistic with 101 F6 decrease tumor growth.       [264]

SCID mice      EHMS-10 mesothelioma cells     Asc 0.88, 8.8 g/mouse, i.v. single dose.      Decrease tumor growth.      [265]

Balb/c mice   Murine sarcoma S180 cells  Asc 5.5, 30 mg/mouse, i.p., every two days.      Decrease tumor growth; inhibit bFGF, VEGF and MMP2 genes.       [266]

Balb/c mice   Murine sarcoma S180 cells  Asc 1.5 mg/g, i.p., every three days.       Inhibit tumor establishment; RKIP and annexin A5 levels increase. [267]

 

9. Perspectives

The inhibition effects of pharmacologic ascorbate on tumor growth have been confirmed in many laboratories (Table 4). In murine models elevated ascorbate levels in plasma were verified following i.p. administration [11,164]. It is still unknown whether cells and tissues levels are also elevated [226,227]. Human platelets supplemented with 500 M Asc for 30 min showed a decrease in SVCT2 levels, while in Asc depleted platelets SVCT2 expression was higher than native ones [29]. Thus in vivo studies for possible changes in SVCT expression levels following ascorbate infusion are needed. Another issue is a possible transient withdrawal effect upon cessation of treatment with pharmacologic ascorbate [228]. Male guinea pigs that received ascorbate 1 g kg1 body weight per day by i.p. for 4 weeks had elevated plasma and urinary levels; however, in the weeks after the treatment withdrawn, mean plasma and urinary ascorbate were significantly lower than normal [229]. It is unknown if a similar rebound effect would occur in human subjects following high doses i.v. ascorbate. F2-isoprostane is a biomarker for lipid peroxidation in vivo, and its quantification in plasma and urine has emerged as the most reliable method to assess systemic oxidative stress in humans and animals [230C232]. For healthy young women taking oral doses of ascorbate 30C2500 mg daily, plasma and urine F2-isoprostanes were unchanged [41]. It is unclear whether plasma F2-isoprostanes will change following pharmacologic ascorbate infusion in cancer patients. Furthermore, since pharmacological ascorbate is a prodrug for H2O2 generation, there should be many applications where delivery of H2O2 via pharmacological ascorbate may have clinical benefit, such as infectious diseases caused by viruses, bacteria, and other pathogens [10,233].

 

 

Summary

More than eighty years since its discovery, our understanding of the functions of ascorbic acid has evolved from the prevention of scurvy to its potential use as a therapeutic drug for cancer treatment. Ascorbate maintains Fe2+ of collagen hydroxylases in an active state; therefore it plays a pivotal role in collagen synthesis; parallel reactions with a variety of dioxygenases affect the expression of a wide array of genes, for example via the HIF system, and possibly the epigenetic landscape of cells and tissues. The ability to donate one or two electrons makes ascorbate an excellent reducing agent and antioxidant. However, in the presence of catalytic metals, ascorbate also has pro-oxidant effects, where the redox-active metal is reduced by ascorbate and then in turn reacts with oxygen, producing superoxide that subsequently dismutes to produce H2O2.

 

Apart from its biochemical functions that are met by healthy nutritional levels, recent pharmacokinetic data indicate that intravenous administration of ascorbate bypasses the tight control of the gut and renal excretion; thus, intravenous administration of ascorbate will produce highly elevated plasma levels; this ascorbate will autoxidize resulting in a high flux of extracellular H2O2. This H2O2 will readily diffuse into cells challenging the intracellular peroxide-removal system, initiating oxidative cascades. These high fluxes of H2O2 appear to have little effect on normal cells but can be detrimental to certain tumor cells. Knowledge and understanding of these mechanisms brings a rationale to the use of high-dose ascorbate to treat disease and thereby is reviving interest in the use of i.v. ascorbate in cancer treatment. The full potential of pharmacological ascorbate in cancer treatment will only be realized with greater understanding of its basic mechanism of action in conjunction with the appropriate design of clinical trials.

 

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Abbreviations

Asc  a general abbreviation to include all forms, i.e. AscH2 +AscH+Asc2+DHA

AscH2    ascorbic acid, vitamin C

AscH    ascorbate monoanion

Asc2    ascorbate dianion

Asc•     semidehydroascorbate, i.e. ascorbate radical

DHA       dehydroascorbic acid

HIF  hypoxia inducible factor

PDI  protein disulfide isomerase

SVCT      sodium-dependent vitamin C transporters

 

Biochim Biophys Acta. Author manuscript; available in PMC 2013 Dec 1.

Published in final edited form as:

Biochim Biophys Acta. 2012 Dec; 1826(2): 443C457.

Published online 2012 Jun 20. doi:  [10.1016/j.bbcan.2012.06.003]

PMCID: PMC3608474

NIHMSID: NIHMS401995

PMID: 22728050

Ascorbic acid: Chemistry, biology and the treatment of cancer

Juan Du,a Joseph J. Cullen,a,b,c,d and Garry R. Buettnera,c,*

Author information Copyright and License information Disclaimer

aDepartment of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA, USA

bDepartment of Surgery, University of Iowa College of Medicine, Iowa City, IA, USA

cHolden Comprehensive Cancer Center, USA

dVeterans Affairs Medical Center, Iowa City, IA, USA

*Corresponding author at: Department of Radiation Oncology, Free Radical and Radiation Biology, Med Labs B180, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Tel.: +1 319 335 8015 (office), +1 319 335 8019 (secretary); fax: +1 319 335 8039. ude.awoiu@rentteub-yrrag (G.R. Buettner)

 

Ascorbic acid: Chemistry, biology and the treatment of cancer  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608474/