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

Parrow, Nermi L.; Leshin, Jonathan A.; Levine, Mark

doi:10.1089/ars.2013.5372

Cited by 86 publications

(116 citation statements)

References 75 publications

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“…Treatment with 1 or 5 mM ascorbate increased the levels of intracellular ROS in ReN cells but not in mesothelium cells. Additionally, it was demonstrated that malignant mesothelioma cells enhanced superoxide production and induced overexpression of the superoxide-producing NADPH oxidase 4 (47). This discrepancy between data collected in the current study and previous studies may be due to different doses of agents used, duration of treatments and the sequential treatments that were employed.…”

Section: Discussioncontrasting

confidence: 89%

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

et al. 2017

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Abstract.The balance between the production and elimination of reactive oxygen species (ROS) is essential in determining whether cells survive or undergo apoptosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) may act as a sensor for electrophilic stress, thus regulating the intracellular antioxidant response. The present study investigated the role of vitamin C (VC) and quercetin (Q) in the induction of Nrf2-mediated oxidative stress in cancer cells. An MTT assay was conducted to examine the anti-proliferative effects of VC and Q. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to determine the messenger RNA (mRNA) and protein expression of Nrf2, respectively. The activity of nicotinamide adenine dinucleotide phosphate dehydrogenase quinone 1, heme oxygenase 1, glutathione peroxidase, glutathione reductase and reduced glutathione were measured by spectrophotometric analysis. Intracellular generation of ROS was determined using 2'-7'-dichlorodihydrofluorescein diacetate fluorescent probes. The results demonstrated that the cytotoxicity (50% inhibitory concentration) of VC and Q were 271.6-480.1 and 155.1-232.9 µM, respectively. Additionally, there was a significant decrease in the expression of Nrf2 mRNA and protein levels following the treatment of breast cancer cells with VC and Q (P=0.024). Following treatment with VC and Q, the nuclear/cytosolic Nrf2 ratio was reduced by 1.7-fold in MDA-MB 231 cells, 2-fold in MDA-MB 468 cells, 1.4-fold in MCF-7 cells and 1.2 fold in A549 cells. Sequential treatment with VC and Q decreased endogenous production of ROS in a dose-dependent manner (P=0.027). The results of the current study suggest that VC and Q treatment may be developed as an adjuvant for patients with cancer and overexpression of Nrf2.

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Section: Discussioncontrasting

confidence: 89%

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

et al. 2017

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“…The benefit of high doses of ascorbate in broad-spectrum cancer treatment was initially reported by Cameron and Pauling [77]; however, subsequent trials have either shown promising benefits in certain circumstances, or have provided no detectable advantages at all [78][79][80][81][82][83][84]. Nevertheless, it remains possible that vitamin C supplementation can reverse global loss of 5hmC [6] and hypermethylation of tumor-suppressor genes [75,76].…”

Section: Reprogrammingmentioning

confidence: 99%

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Hore

2017

Epigenomics

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Vitamins A and C represent unrelated sets of small molecules that are essential to the human diet and have recently been shown to intensify erasure of epigenetic memory in naive embryonic stem cells. These effects are driven by complementary enhancement of the ten-eleven translocation (TET) demethylases -vitamin A stimulates TET expression, whereas vitamin C potentiates TET catalytic activity. Vitamin A and C cosupplementation synergistically enhances reprogramming of differentiated cells to the naive state, but overuse may exaggerate instability of imprinted genes. As such, optimizing their use in culture media will be important for regenerative medicine and mammalian transgenics. In addition, mechanistic perception of how these vitamins interact with the epigenome may be relevant for understanding cancer and improving patient treatment. Figure 1A), and both are associated with a long recorded history. Nightblindness, an early symptom of vitamin A deficiency, and its cure through liver consumption, was known to Egyptians in the prehistoric period [1]. Equally, the debilitating effects of scurvy (vitamin C deficiency) among sailors, and its treatment with oranges, was registered as far back as 1498 [2]. Vitamins A and C also have a lengthy and rich history in scientific literature; in 1753 James Lind described the first controlled clinical trial where various antiscorbutic treatments were tested on British seamen and in 1929, Frederick Gowland Hopkins was co-awarded the Nobel Prize in Medicine for the 'discovery of vitamins' following milk supplementation experiments in vitamin A deficient mice [3]. Eventual isolation of the respective compounds underlying both vitamins led to Nobel Prizes in Chemistry and Medicine in 1937 [4]. Since this time, a considerable amount of scientific progress (and at times conjecture) has been associated with vitamins A and C, and their respective biological effects touch disciplines as divergent as development and dermatology.One of the most recently discovered fields that vitamins A and C impact upon is epigenetics [5][6][7]. New research has shown that both vitamins drive active removal of DNA methylation in embryonic stem cells (ESCs) by enhancing the same family of ten-eleven translocation (TET) enzymes, and in doing so, help erase DNA methylation and the epigenetic memory encoded by it to improve the reprogramming of differentiated cells to an embryonic-like state. Here I review the effects of vitamins A and C on DNA methylation and epigenetic memory in stem cells, and outline their significance for the fields For reprint orders, please contact: reprints@futuremedicine.com

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

Cited by 86 publications

References 75 publications

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

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

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