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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: 9.81). 08/2008; 105(32):11105-9. DOI: 10.1073/pnas.0804226105
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ABSTRACT 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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    • "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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    • "Chen and colleagues reported that normal cells are resistant to high dose ascorbate in vitro and that the sensitivity to high dose ascorbate differs between cancer cells even within the same tumor type. However to our knowledge, no one has reported on the sensitivity of HUVECs or normal glial cells to high dose ascorbate [12]. Cells had either strong antioxidant capacity or effective DNA repair. "
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    Free Radical Biology and Medicine 06/2014; 74. DOI:10.1016/j.freeradbiomed.2014.06.022 · 5.71 Impact Factor
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    • "Vitamin C is a water-soluble nutrient that has been hypothesised to influence cancer initiation and promotion through its antioxidant properties including the neutralization of free radicals (Frei, 1994; Willcox et al, 2004). In addition, in vitro experiments have shown cytotoxic action of vitamin C against cancer cells without subsequent toxicity to normal cells (Chen et al, 2008; Ullah et al, 2011). However, the evidence from observational epidemiologic studies on vitamin C intake and survival following breast cancer diagnosis is not consistent, with dietary vitamin C intake reported to reduce the risk of mortality in some studies (Rohan et al, 1993; Ingram, 1994; Jain et al, 1994; Fleischauer et al, 2003; McEligot et al, 2006) and no association in other studies (Zhang et al, 1995; Hebert et al, 1998; Holmes et al, 1999; Saxe et al, 1999; Saquib et al, 2011). "
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