Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci USA

Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2008; 105(32):11105-9. DOI: 10.1073/pnas.0804226105
Source: PubMed


Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.

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    • "It was found that high dose intravenous vitamin C was safe, and ascorbate concentrations that could effectively slow tumor growth in animals could also be achieved in humans. Our study in 2008 demonstrated that, with intravenous doses of 75–100 g, ascorbate concentrations as high as 25 mmol/L were safely achieved and sustained for several hours (Padayatty et al. 2004; Chen et al. 2008), which is a concentration sufficient to induce death in many cancer cells. In the same year, Hoffer et al. reported that in cancer patients, i.v. "
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    ABSTRACT: Effectiveness and low-toxicity to normal tissues are ideal properties for a cancer treatment, and one that numerous research programs are aiming for. Vitamin C has long been used in the field of Complementary and Alternative Medicine as a cancer treatment, with profound safety and anecdotal efficacy. Recent studies revealed the scientific basis for this use, and indicated that vitamin C, at supra-nutritional doses, holds considerable promise as an effective and low-toxic therapeutic strategy to treat cancer. Reviewed here are the early controversies surrounding vitamin C and cancer treatment, the breakthrough discoveries that led to the current advancement, and recent clinical studies, as well as research into its mechanisms of action.
    Canadian Journal of Physiology and Pharmacology 05/2015; DOI:10.1139/cjpp-2014-0509 · 1.77 Impact Factor
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    • "Despite encouraging anecdotal reports and promising results in xenograft models (5, 6, 111, 112), the initial formal phase I clinical trials of intravenous high-dose ascorbate therapy for cancer have so far yielded little evidence of objective response (2, 113). The possibility that ascorbate therapy can improve the response to concurrent chemotherapies, as suggested in rodent studies, is now under active investigation (6, 105, 114, 115). "
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    ABSTRACT: Low millimolar concencentrations of ascorbate are capable of inflicting lethal damage on a high proportion of cancer cells lines, yet leave non-transformed cell lines unscathed; extracellular generation of hydrogen peroxide, reflecting reduction of molecular oxygen by ascorbate, has been shown to mediate this effect. Although some cancer cell lines express low catalase activity, this cannot fully explain the selective sensitivity of cancer cells to hydrogen peroxide. Ranzato and colleagues have presented evidence for a plausible new explanation of this sensitivity - a high proportion of cancers, via NADPH oxidase complexes or dysfunctional mitochondria, produce elevated amounts of superoxide. This superoxide, via a transition metal-catalyzed transfer of an electron to the hydrogen peroxide produced by ascorbate, can generate deadly hydroxyl radical (Haber-Weiss reaction). It thus can be predicted that concurrent measures which somewhat selectively boost superoxide production in cancers will enhance their sensitivity to i.v. ascorbate therapy. One way to achieve this is to increase the provision of substrate to cancer mitochondria. Measures which inhibit the constitutive hypoxia-inducible factor-1 (HIF-1) activity in cancers (such as salsalate and mTORC1 inhibitors, or an improvement of tumor oxygenation), or that inhibit the HIF-1-inducible pyruvate dehydrogenase kinase (such as dichloroacetate), can be expected to increase pyruvate oxidation. A ketogenic diet should provide more lipid substrate for tumor mitochondria. The cancer-killing activity of 42°C hyperthermia is to some degree contingent on an increase in oxidative stress, likely of mitochondrial origin; reports that hydrogen peroxide synergizes with hyperthermia in killing cancer cells suggest that hyperthermia and i.v. ascorbate could potentiate each other’s efficacy. A concurrent enhancement of tumor oxygenation might improve results by decreasing HIF-1 activity while increasing the interaction
    Frontiers in Oncology 09/2014; 4:249. DOI:10.3389/fonc.2014.00249
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    • "y dependent on absorption through functional vitamin C transporters ( Savini et al . , 2008 ) . Due to its antioxidant nature causing neutralization of free radicals , AA has been postulated to inhibit cancer initiation and promotion ( Harris et al . , 2013 ) . Several reports have suggested the cytotoxic action of vitamin C against cancer cells ( Chen et al . , 2008 ; Ullah et al . , 2011 ) . Also , the evidence from various epidemiologic studies cited the role of vitamin C as controversial in breast cancer ( Harris et al . , 2013 ) . All these biological progressions put emphasis on having a thorough understanding of the mechanism of AA transport in breast cancer cell lines . The main goal of this"
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    ABSTRACT: The main goal of this study is to investigate the expression of sodium dependent vitamin C transport system (SVCT2). Moreover this investigation has been carried out to define uptake mechanism and intracellular regulation of ascorbic acid (AA) in human breast cancer cells (MDA-MB231, T47D and ZR-75-1). Uptake of [(14)C] AA was studied in MDA-MB231, T47D and ZR-75-1cells. Functional parameters of [(14)C] AA uptake were delineated in the presence of different concentrations of unlabeled AA, pH, temperature, metabolic inhibitors, substrates and structural analogs. Molecular identification of SVCT2 was carried out with reverse transcription-polymerase chain reaction (RT-PCR). Uptake of [(14)C] AA was studied and found to be sodium, chloride, temperature, pH and energy dependent in all breast cancer cell lines. [(14)C] AA uptake was found to be saturable, with Km values of 53.85±6.24, 49.69±2.83 and 45.44±3.16μM and Vmax values of 18.45±0.50, 32.50±0.43 and 33.25±0.53pmol/min/mg protein, across MDA-MB231, T47D and ZR-75-1, respectively. The process is inhibited by structural analogs (L-AA and D-Iso AA) but not by structurally unrelated substrates (glucose and PAHA). Ca(++)/calmodulin and protein kinase pathways appeared to play a crucial role in modulating AA uptake. A 626bp band corresponding to a vitamin C transporter (SVCT2) based on the primer design was detected by RT-PCR analysis in all breast cancer cell lines. This research article describes AA uptake mechanism, kinetics, and regulation by sodium dependent vitamin C transporter (SVCT2) in MDA-MB231, T47D and ZR-75-1cells. Also, MDA-MB231, T47D and ZR-75-1 cell lines can be utilized as a valuable in vitro model to investigate absorption and permeability of AA-conjugated chemotherapeutics.
    International Journal of Pharmaceutics 08/2014; 474(1-2). DOI:10.1016/j.ijpharm.2014.07.056 · 3.65 Impact Factor
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