Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice

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
Source: PubMed

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.

Download full-text


Available from: Qi Chen, Jul 08, 2015
  • Source
    • "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"
    [Show abstract] [Hide abstract]
    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 · 3.79 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously showed that 5mM ascorbate radiosensitized early passage radioresistant glioblastoma multiforme (GBM) cells derived from one patient tumour. Here we investigate the sensitivity of a panel of cell lines to 5mM ascorbate and 6Gy ionising radiation, made up of three primary human GBM cells, three GBM cell lines, a human glial cell line and primary human vascular endothelial cells. The response of different cells lines to ascorbate and/or radiation was determined by measuring viability, colony-forming ability, generation and repair of double stranded DNA breaks (DSBs), cell cycle progression, antioxidant capacity and generation of reactive oxygen species. Individually, radiation and ascorbate both decreased viability and clonogenicity by inducing DNA damage, but had differential effects on cell cycle progression. Radiation led to G2/M arrest in most cells whereas ascorbate caused accumulation in S-phase, which was moderately associated with poor DSB repair. While high dose ascorbate radio-sensitized all cell lines in clonogenic assays, the sensitivity to radiation, high dose ascorbate and combined treatment varied between cell lines. Normal glial cells were similar to GBM cells with respect to free radical scavenging potential and effect of treatment on DNA damage and repair, viability and clonogenicity. Both GBM cells and normal cells coped equally poorly with oxidative stress caused by radiation and/or high dose ascorbate, dependent primarily on their antioxidant and DSB repair capacity.
    Free Radical Biology and Medicine 06/2014; 74. DOI:10.1016/j.freeradbiomed.2014.06.022 · 5.71 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Vitamin C may influence cancer progression through its antioxidant properties. However, the evidence from observational epidemiologic studies on vitamin C intake and survival following breast cancer diagnosis is not consistent, and the safety of vitamin C supplements following breast cancer diagnosis has not been extensively studied. Methods: Using a food-frequency questionnaire we investigated whether vitamin C intake was associated with survival among 3405 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. Results: From 1987–2010, there were 1055 total deaths with 416 deaths from breast cancer. Women in the highest quartile of pre-diagnosis vitamin C intake had an adjusted HR (95% CI) of breast cancer death of 0.75 (0.57–0.99) compared with those in the lowest quartile (Ptrend=0.03). There was a borderline significant association between vitamin C intake and total mortality (HR=0.84; 95% CI=0.71–1.00; Ptrend=0.08). Among 717 breast cancer cases for whom post-diagnosis supplement use was available, there was no association between vitamin C supplement use (≈1000 mg) and breast cancer-specific mortality (HR=1.06; 95% CI=0.52–2.17). Conclusion: Our findings suggest that dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. In addition, post-diagnosis vitamin C supplementation at the level observed in our population was not associated with survival.
    British Journal of Cancer 06/2013; 109(1). DOI:10.1038/bjc.2013.269 · 4.82 Impact Factor