Comment re: Vitamin C Antagonizes the Cytotoxic Effects of Chemotherapy

Espey, Michael Graham; Chen, Qi; Levine, Mark

doi:10.1158/0008-5472.can-08-3798

Cited by 7 publications

(6 citation statements)

References 7 publications

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“…However, a striking 96% of individuals currently diagnosed with pancreatic adenocarcinoma have nonresectable, locally advanced, or metastatic disease [7], for whom few therapeutic options are available to abate a rapid disease progression. Although some have suggested interference of vitamin C with chemotherapy [59], investigators in that supporting study used the ascorbate metabolite dehydroascorbic acid, at concentrations that are toxic in humans and could not be produced from either physiologic or pharmacologic ascorbate [13,59,60]. This study clearly provides evidence that pharmacologic ascorbate can improve gemcitabine therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 85%

Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

Espey

Chen

Chalmers

et al. 2011

Free Radical Biology and Medicine

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153

143

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Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial–mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H2O2 derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine–ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer.

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Section: Discussionmentioning

confidence: 85%

Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

Espey

Chen

Chalmers

et al. 2011

Free Radical Biology and Medicine

Self Cite

153

143

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“…As noted elsewhere, the concentration of dehydroascorbic acid used is biologically irrelevant and potentially harmful. The results cannot be extrapolated to the effects of ascorbate (25,63).…”

Section: Synergy and Antagonism Of Chemotherapeuticsmentioning

confidence: 88%

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Parrow

Leshin

Levine

2013

Antioxidants & Redox Signaling

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110

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Significance: Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10 g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. However, the route of administration results in major differences in ascorbate bioavailability. Tissue and plasma concentrations are tightly controlled in response to oral administration, but this can be bypassed by intravenous administration. These data provide a plausible scientific rationale for the absence of a response to orally administered ascorbate in the Mayo clinic trials and indicate the need to reassess ascorbate as a cancer therapeutic. Recent Advances: High dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide (H 2 O 2 ). Murine xenograft models confirm a growth inhibitory effect of pharmacological concentrations. The safety of intravenous ascorbate has been verified in encouraging pilot clinical studies. Critical Issues: Neither the selective toxicity of pharmacologic ascorbate against cancer cells nor the mechanism of H 2 O 2 -mediated cytotoxicity is fully understood. Despite promising preclinical data, the question of clinical efficacy remains. Future Directions: A full delineation of mechanism is of interest because it may indicate susceptible cancer types. Effects of pharmacologic ascorbate used in combination with standard treatments need to be defined. Most importantly, the clinical efficacy of ascorbate needs to be reassessed using proper dosing, route of administration, and controls.

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“…Oral ascorbate produces concentrations in plasma and tissue which are tightly controlled (<0.2 mM), while pharmacological concentrations of ascorbate in plasma (≫0.2 mM), which may lead to tumor cytotoxicity, can only be achieved by parenteral administration. Furthermore, there is some scientific debate regarding the therapeutic relevance and efficacy of ascorbate versus dehydroascorbate ([15, 20, 26]; see below).…”

Section: Introductionmentioning

confidence: 99%

Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs

Frömberg

Gutsch

Schulze

et al. 2010

Cancer Chemother Pharmacol

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PurposeWhile the benefits of ascorbic acid (vitamin C, ascorbate) as an essential nutrient are well established, its effects on tumor cells and in tumor treatment are controversial. In particular, conflicting data exist whether ascorbate may increase the cytotoxic effects of antineoplastic drugs or may rather exert adverse effects on drug sensitivity during cancer treatment. Findings are further obscured regarding the distinction between ascorbate and dehydroascorbate (DHA). Thus, the purpose of this study was to evaluate and directly compare the cytotoxic efficacy of ascorbate compared to DHA, and to analyse if ascorbate at pharmacological concentrations affects the efficacy of antineoplastic agents in prostate carcinoma cells.MethodsWe directly compare the effects of ascorbate (supplied as ‘Pascorbin® solution for injection’) and DHA on tumor cell viability, and determine IC50 values for various cell lines. At concentrations well below the IC50, ascorbate effects on cell proliferation and cell cycle are analysed. We furthermore determine changes in cellular sensitivity towards various cytostatic drugs upon pre-treatment of cells with ascorbate.ResultsWe demonstrate higher therapeutic efficacy of ascorbate over DHA in various cell lines, independent of cell line-specific differences in ascorbate sensitivity, and identify the extracellular generation of H2O2 as critical mechanism of ascorbate action. We furthermore show that, in addition to pro-apoptotic effects described previously, ascorbate treatment already at concentrations well below the IC50 exerts anti-proliferative effects on tumor cells. Those are based on interference with the cell cycle, namely by inducing a G0/G1 arrest. Pre-treatment of tumor cells with ascorbate leads to increased cellular sensitivity towards Docetaxel, Epirubicin, Irinotecan and 5-FU, but not towards Oxaliplatin and Vinorelbin. For Docetaxel and 5-FU, a linear correlation between this sensitizing effect and the ascorbate dosage is observed.ConclusionsThe redox-active form of vitamin C, ascorbate, shows therapeutic efficacy in tumor cells. These antitumor effects of ascorbate are mainly based on its extracellular action and, in addition to the induction of apoptosis, also include an anti-proliferative effect by inducing cell cycle arrest. Furthermore, ascorbate treatment specifically enhances the cytostatic potency of certain chemotherapeutics, which implicates therapeutic benefit during tumor treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-010-1418-6) contains supplementary material, which is available to authorized users.

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Comment re: Vitamin C Antagonizes the Cytotoxic Effects of Chemotherapy

Cited by 7 publications

References 7 publications

Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs

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