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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    • ") and ultimately the tumoricidal H 2 O 2[40,464748. Herein, we compiled a H 2 O 2 -responsive chemotherapeutic drug (camptothecin: CPT) delivery nanocarrier supplemented with PA through formation of polymer prodrug-PA hybrid micelles (HPMs) (Scheme 1). The strategic incorporation of PA is postulated to endow the nanocarriers with selfsufficing H 2 O 2 stimuli, which specifically elevate tumoral H 2 O 2 level via H 2 O 2 production not only improving oxidative stress to the tumors but also triggering CPT release from the delivery nanovehicles. "
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    ABSTRACT: One of distinct features in tumor tissues is the elevated concentration of reactive oxygen species (ROS) during tumor immortality, proliferation and metastasis. However, ROS-responsive materials are rarely utilized in the field of in vivo tumoral ROS-responsive applications due to the fact that the intrinsic ROS level in the tumors could not escalate to an adequate level that the developed materials can possibly respond. Herein, palmitoyl ascorbate (PA) as a prooxidant for hydrogen peroxide (H2O2) production in tumor tissue is strategically compiled into a H2O2-responsive camptothecin (CPT) polymer prodrug micelle, which endowed the nanocarriers with self-sufficing H2O2 stimuli in tumor tissues. Molecular oncology manifests the hallmarks of tumoral physiology with deteriorating propensity in eliminating hazardous ROS. H2O2 production was demonstrated to specifically sustain in tumors, which not only induced tumor cell apoptosis by elevated oxidation stress but also served as autochthonous H2O2 resource to trigger CPT release for chemotherapy. Excess H2O2 and released CPT could penetrate into cells efficiently, which showed synergistic cytotoxicity toward cancer cells. Systemic therapeutic trial revealed potent tumor suppression of the proposed formulation via synergistic oxidation-chemotherapy. This report represents a novel nanomedicine platform combining up-regulation of tumoral H2O2 level and self-sufficing H2O2-responsive drug release to achieve novel synergistic oxidation-chemotherapy.
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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.
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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
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