Anti-angiogenic effect of high doses of ascorbic acid

Mikirova, Nina; Ichim, Thomas E.; Riordan, Neil H

doi:10.1186/1479-5876-6-50

Cited by 71 publications

(63 citation statements)

References 36 publications

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“…In this study, the formation of basement membrane around the tubules was impaired in the absence of AA (data not shown). However, AA inhibited angiogenesis at high concentrations (1000-2000 µg/ ml) as reported previously (Mikirova et al, 2008). Therefore, AA is essential for collagen IV formation in basement membrane at low concentrations.…”

Section: Discussionmentioning

confidence: 69%

Human vascular model with defined stimulation medium – a characterization study

Huttala

2015

ALTEX

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SummaryThe formation of blood vessels is a vital process in embryonic development and in normal physiology. Current vascular modelling is mainly based on animal biology leading to species-to-species variation when extrapolating the results to humans. Although there are a few human cell based vascular models available, these assays are insufficiently characterized in terms of culture conditions and developmental stage of vascular structures. Therefore, well characterized vascular models with human relevance are needed for basic research, embryotoxicity testing, development of therapeutic strategies and for tissue engineering. We have previously shown that the in vitro vascular model based on co-culture of human adipose stromal cells (hASC) and human umbilical vein endothelial cells (HUVEC) is able to induce an extensive vascular-like network with high reproducibility. In this work we developed a defined serum-free vascular stimulation medium (VSM) and performed further characterization in terms of cell identity, maturation and structure to obtain a thoroughly characterized in vitro vascular model to replace or reduce corresponding animal experiments. The results showed that the novel vascular stimulation medium induced an intact and evenly distributed vascular-like network with morphology of mature vessels. Electron microscopic analysis assured the three-dimensional microstructure of the network containing lumen. Additionally, elevated expression levels of the main human angiogenesis-related genes were detected. In conclusion, with the newly defined medium the vascular model can be utilized as a characterized test system for chemical testing as well as in creating vascularized tissue models.

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Section: Discussionmentioning

confidence: 69%

Human vascular model with defined stimulation medium – a characterization study

Huttala

2015

ALTEX

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“…Our previous research suggests that ascorbate therapy, at the high doses associated with intravenous infusions clinically, can inhibit angiogenesis and reduce tumor inflammation [3,4,17,18]. In study [92], lung blood vessel proliferation and the incidence of pulmonary malignant tumors were reduced in the offspring of mice expose to cigarette smoke and a preventive treatment with ascorbic acid in drinking water throughout the pregnancy.…”

Section: Discussionmentioning

confidence: 93%

“…Ascorbate plays a role in limiting inflammation, regulating cytokine production, and boosting the immune system [2][3][4][5][6][7][8]. It has a variety of properties that have generated interest in using it against cancer [9][10][11][12][13]: it enhances natural killer cell activity [14,15], increases collagen synthesis [16], inhibits capillary tubule formation (angiogenesis) [17,18], reduces inflammation in cancer patients [3], at millimolar concentrations, shows cytotoxicity against cancer cells [19][20][21][22][23][24] and the ability to reduce tumor growth in vivo [25][26][27][28][29][30][31][32][33][34]. Clinical trials to date [35][36][37][38][39][40] indicate that high dose (on the order of ten to 100 grams) intravenous ascorbate therapy can enhance anti-cancer effects of chemotherapy and improve quality of life in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Gene expression response to ascorbic acid in mice implanted with sarcoma S180 cells

Mikirova¹,

Scimeca²

2016

J Transl Sci

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In recent years, increasing numbers of studies demonstrated that high-dose ascorbate, which can be achieved by intravenous infusion, has cytotoxic effects on cancer cells in vitro and in vivo. There are many hypotheses of anti-cancer mechanisms of high dose ascorbate including a pro-oxidative mechanism, inhibition of angiogenesis and inflammation, enhancement of the anticancer effect of chemotherapy and reduction of chemotherapy-induced side effects. In addition, in recent years there were studies showing that ascorbic acid has effect on gene expression and epigenetic phenomena. In our study we analyzed, by using animal model, the effect of pharmacological concentrations of ascorbic acid on several gene expressions involved in tumorigenesis. To test the effects of ascorbic acid on gene expression, we treated mice with two different concentrations of ascorbic acid after intraperitoneal administration with sarcoma S-180 cells. The injected doses of ascorbic acid were equivalent to 15 g per 70 kg human and 50 g per 70 kg human. Tissue from tumors, liver and kidney was obtained from mice at the end of three weeks of treatment. The gene expression analysis was computed by real time PCR. The results showed significant difference in expression of gene p53 (p<0.02) in tumor tissue between treated and non-treated groups, and reduction of p53 gene expression by size and spreading of tumors. Ascorbate therapy significantly increased expression of NRF2. The experimental data showed that the maximum ascorbate dosage reduced expression of the tumor promoting gene HIF. The dependence of gene expression on the size of tumors was found for P53, HIF and NF-kB. In summary, the results of our study demonstrated that ascorbate therapy had a significant effect on the expression of several genes relevant to the development or inhibition of cancer. Reduced expression of tumor promoting genes as HIF and increased expression of tumor suppression genes such as p53 support the hypothesis that ascorbic acid can act as a potential agent for the suppression of tumor development.

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“…Ascorbate treatment was also associated with a dose-dependent decrease in nitric oxide production. Both studies report decreased cell migration in wound repair models (53,82).…”

Section: Effects On Angiogenesismentioning

confidence: 99%

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

Parrow

Leshin

Levine

2013

Antioxidants & Redox Signaling

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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Anti-angiogenic effect of high doses of ascorbic acid

Cited by 71 publications

References 36 publications

Human vascular model with defined stimulation medium – a characterization study

Human vascular model with defined stimulation medium – a characterization study

Gene expression response to ascorbic acid in mice implanted with sarcoma S180 cells

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

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