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Nathan Goodyear

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a p... - 0 views

www.pnas.org/...13604.full

IV vitamin C cancer ascorbic acid vitamin C H2O2 GPX glutathione Perioxidase

shared by Nathan Goodyear on 09 Feb 11 - Cached
  • Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues.
  • These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial
  • pharmacologic concentrations of ascorbate killed cancer but not normal cells, that cell death was dependent only on extracellular but not intracellular ascorbate, and that killing was dependent on extracellular hydrogen peroxide (H2O2) formation with ascorbate radical as an intermediate
  • ...48 more annotations...
  • Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration
  • Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid
  • ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu
  • H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents
  • The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      The mechansism here is inadequate recycling of GSH due to lack of G6PD, build up of intracellular H2O2 and RBC lysis--hemolysis.
  • Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate
  • Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration
  • Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations
  • For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      accumulation of extracellular vitamin C is the effect.
  • It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.
  • There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.
  • H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections
  • Neutrophils generate H2O2 from superoxide,
  • i.v. ascorbate is effective in some viral infections
  • H2O2 is toxic to hepatitis C
  • Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.
  • Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose
  • As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,
  • Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm
  • Human Burkitt's lymphoma cells
  • We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines
  • Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration
  • plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption
  • For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion
  • All tested normal cells were insensitive to 20 mM ascorbate.
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      meaning safe.
  • Lymphoma cells were selected because of their sensitivity to ascorbate
  • As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death
  • Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      work continued beyond the IVC therapy itself
  • In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate
  • Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate
  • Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.
  • extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.
  • H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death
  • Superoxide dismutase was not protective
  • Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate
  • For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased
  • Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes
  • There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity
  • H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media
  • ascorbate radical is a surrogate marker for H2O2 formation.
  • whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable
  • The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.
  • The occurrence of one predicted complication, oxalate kidney stones, is controversial
  • In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis
  • ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.
  • ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation
  • data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      the conversion of ascorbate to H2O2 occurs extracellular
  • More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis
  • Nathan Goodyear on 09 Feb 11
     
    IV vitamin C benefits cancer patients
Nathan Goodyear

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC4537815

cancer pancreatic cancer IV vitamin C vitamin c radiation

shared by Nathan Goodyear on 30 Jan 18 - No Cached
  • Previous studies from our laboratory have demonstrated that pharmacological ascorbate is cytotoxic to pancreatic cancer cells while normal cells are resistant
  • Ascorbate-induced cytotoxicity is mediated by the formation of H2O2 during the oxidation of ascorbate
  • the combination of IR + ascorbate increased the concentration of intracellular H2O2
  • ...17 more annotations...
  • Under steady-state conditions, intracellular GSH is maintained at millimolar concentrations, which keeps cells in a reduced environment and serves as the principal intracellular redox buffer when cells are subjected to an oxidative stressor including H2O2 (26). Glutathione peroxidase (GPx) activity catalyzes the reduction of H2O2 to water with the conversion of GSH to glutathione disulfide (GSSG). Under steady-state conditions, GSSG is recycled back to GSH by glutathione disulfide reductase using reducing equivalents from NADPH. However, under conditions of increased H2O2 flux, this recycling mechanism may become overwhelmed leading to a depletion of intracellular GSH (27, 28).
  • ascorbate radiosensitization can create an overwhelming oxidative stress to pancreatic cancer cells resulting in oxidation/depletion of the GSH intracellular redox buffer, resulting in cell death.
  • Treatment with the combination of ascorbate + IR significantly delayed tumor growth compared to controls or ascorbate alone
  • Ascorbate + IR also significantly increased overall survival compared to controls, IR alone or ascorbate alone
  • 54% of mice treated with the combination of IR + ascorbate had no measurable tumors
  • Glutathione is a measurable marker indicative of the oxidation state of the thiol redox buffer in cells. In severe systemic oxidative stress, the GSSG/2GSH couple may become oxidized, i.e. the concentration of GSH decreases and GSSG may increase because the capacity to recycle GSSG to GSH becomes rate-limiting
  • This suggests that the very high levels of pharmacological ascorbate in these experiments may have a pro-oxidant toward red blood cells as seen by a decrease in the capacity of the intracellular redox buffer
  • These data support the hypothesis that ascorbate radiosensitization does not cause an increase in oxidative damage from lipid-derived aldehydes to other organs.
  • Our current study demonstrates the potential for pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
  • pharmacological ascorbate enhances IR-induced cell killing and DNA fragmentation leading to induction of apoptosis in HL60 leukemia cells
  • pharmacological ascorbate significantly decreases clonogenic survival and inhibits the growth of all pancreatic cancer cell lines as a single agent, as well as sensitizes cancer cells to IR
  • Hurst et al. demonstrated that pharmacological ascorbate combined with IR leads to increased numbers of double-strand DNA breaks and cell cycle arrest when compared to either treatment alone
  • pharmacological ascorbate could serve as a “pro-drug” for the delivery of H2O2 to tumors
  • the double-strand breaks induced by H2O2 were more slowly repaired
  • The combination of ascorbate and IR provide two distinct mechanisms of action: ascorbate-induced toxicity due to extracellular production of H2O2 that then diffuses into cells and causes damage to DNA, protein, and lipids; and radiation-induced toxicity as a result of ROS-induced damage to DNA. In addition, redox metal metals like Fe2+ may play an important role in ascorbate-induced cytotoxicity. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of H2O2; labile iron can also react with H2O2. Recently our group has demonstrated that pharmacological ascorbate and IR increase the labile iron in tumor homogenates from this murine model of pancreatic cancer
  • we demonstrated that ascorbate or IR alone decreased tumor growth, but the combination treatment further inhibited tumor growth, indicating that pharmacological ascorbate is an effective radiosensitizer in vivo
  • data suggest that pharmacological ascorbate may protect the gut locally by decreasing IR-induced damage to the crypt cells, and systemically, by ameliorating increases in TNF-α
  • Nathan Goodyear on 30 Jan 18
     
    IV vitamin C effective as radiosensitizer in pancreatic cancer.
Nathan Goodyear

Clinical experience with intravenous administration of ascorbic acid: achievable levels... - 0 views

www.ncbi.nlm.nih.gov/...PMC3751545

IV vitamin C dosing ascorbic acid inflammation disease cancer IV vitamin C intravenous vitamin C IV intravenous vitamin C vitamin C CRP therapy treatment alternative

shared by Nathan Goodyear on 26 Aug 14 - No Cached
  • Patients with higher tumor markers are likely to have higher tumor burden, higher oxidative stress and, therefore, are more likely to have lower post IVC plasma levels.
  • Our data also showed that cancer patients with metastasis tend to have lower post-IVC vitamin C levels than those without metastasis
  • Lower peak plasma concentrations are obtained in cancer patients than in healthy subjects. Cancer patients who are deficient in vitamin C prior to therapy tend to achieve lower plasma levels post infusion.
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  • Patients with higher inflammation or tumor burdens, as measured by CRP levels or tumor antigen levels, tend to show lower peak plasma ascorbate levels after IVC.
  • Patients with metastatic tumors tend to achieve lower post infusion plasma ascorbate levels than those with localized tumors.
  • Meta-analyses of clinical studies involving cancer and vitamins also conclude that antioxidant supplementation does not interfere with the efficacy of chemotherapeutic regiments
  • Most of the prostate cancer patients studied, 75±19% (95% confidence), showed reductions in PSA levels during the course of their IVC therapy
  • Laboratory studies suggest that, at high concentrations, ascorbate does not interfere with chemotherapy or irradiation and may enhance efficacy in some situations
  • Cameron and Pauling observed fourfold survival times in terminal cancer patients treated with intravenous ascorbate infusions followed by oral supplementation
  • The inflammatory microenvironment of cancer cells leads to increasing oxidative stress, which apparently depletes vitamin C, resulting in lower plasma ascorbate concentrations in blood samples post IVC infusion. Another explanation for this finding may be that cancers are themselves more metabolically active in their uptake of vitamin C, causing subjects to absorb more of the vitamin, and as a results show lower plasma ascorbate concentrations in blood post IVC infusion.
  • patients with severely elevated CRP levels attain plasma ascorbate concentrations after IVC infusions that are only 65% of those attained for subjects with normal CRP levels
  • The finding of decreased plasma ascorbate levels in cancer patients may relate to the molecular structure of ascorbic acid; in particular, the similarity of its oxidized form, dihydroascorbic acid, to glucose
  • Since tumor have increased requirement for glucose [67], transport of dehydroascorbate into the cancer cells via glucose transport molecules and ascorbate through sodium-dependent transporter may be elevated
  • Increased accumulation of ascorbic acid in the tumor site was supported by measurements of the level of ascorbic acid in tumors in animal experiments
  • patients with advanced malignancies may have lower level of ascorbic acid in tissue, creating a higher demand for the vitamin C
  • IVC therapy appears to reduce CRP levels in cancer patients.
  • CRP concentrations directly correlate with disease activity in many cases and can contribute to disease progression through a range of pro-inflammatory properties.
  • Being an exquisitely sensitive marker of systemic inflammation and tissue damage, CRP is very useful in screening for organic disease and monitoring treatment responses
  • ncreases in CRP concentrations have been associated with poorer prognosis of survival in cancer patients, particularly with advance disease independent of tumor stage
  • Regarding inflammation, 73±13% of subjects (95% confidence) showed a reduction in CRP levels during therapy. This was an even more dramatic 86±13% (95% confidence) in subjects who started therapy with CRP levels above 10 mg/L
  • patients treated by IVC with follow-up several year showed that suppression of inflammation in cancer patients by high-dose IVC is feasible and potentially beneficial
  • Inflammation is a marker of high cancer risk, and poor treatment outcome
  • The subjects with highly elevated CRP concentrations have a three-fold elevation “all-cause” mortality risk and a twenty-eight fold increase in cancer mortality risk
  • cancer patients may need higher doses to achieve a given plasma concentration.
  • patients with lower vitamin C levels may see more distribution of intravenously administered ascorbate into tissues and thus attain less in plasma.
  • When treating patients with IVC, the first treatment likely serves to replenish depleted tissue stores, if those subjects were vitamin C deficient at the beginning of the treatment. Then, in subsequent treatments, with increasing doses, higher plasma concentrations can be attained. On-going treatments serve to progressively reduce oxidative stress in cancer patients.
  • large doses given intravenously may result in maximum plasma concentrations of roughly 30 mM, a level that has been shown to be sufficient for preferential cytotoxicity against cancer cells
  • oral intake of vitamin C exceeded 200 mg administered once daily, it was difficult to increase plasma and tissue concentrations above roughly 200 μM.
  • Nathan Goodyear on 26 Aug 14
     
    Great review on the use of IV vitamin C in cancer and to reduce inflammation.  The article does a great job of discussing the mechanism of vitamin C therapy in cancer as well as the proposed reasons for low vitamin C in cancer patients.  The study also highlights the obstacles to rise in vitamin C levels post IV vitamin C in cancer patients.
Nathan Goodyear

Ascorbic acid: Chemistry, biology and the treatment of cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC3608474

Fenton reaction ferritin vitamin C Fe cancer

shared by Nathan Goodyear on 07 Jul 19 - No Cached
  • iron and ascorbate has long been used as an oxidizing system; the combination of these two reagents is referred to as the Udenfriend system
  • ascorbate serves as a reducing cofactor for many enzymes
  • uptake of ascorbate from the intestinal tract is very tightly controlled
  • ...11 more annotations...
  • pharmacokinetic data indicate that intravenous administration of ascorbate can bypass this tight control resulting in highly elevated plasma levels
  • ascorbate readily oxidizes to produce H2O2, pharmacological ascorbate has been proposed as a prodrug for the delivery of H2O2 to tumors
  • Ascorbate is an excellent reducing agent and readily undergoes two consecutive, one-electron oxidations to form ascorbate radical (Asc•−) and dehydroascorbic acid (DHA)
  • Ascorbate oxidizes readily. The rate of oxidation is dependent on pH and is accelerated by catalytic metals
  • In near-neutral buffers with contaminating metals, the oxidation and subsequent loss of ascorbate can be very rapid
  • Ascorbate is required for maintaining iron in the ferrous state
  • In the presence of catalytic metal ions, ascorbate can also exert pro-oxidant effects
  • Ascorbate is an excellent one-electron reducing agent that can reduce ferric (Fe3+) to ferrous (Fe2+) iron, while being oxidized to ascorbate radical
  • In a classic Fenton reaction, Fe2+ reacts with H2O2 to generate Fe3+ and the very oxidizing hydroxyl radical
  • e presence of ascorbate can allow the recycling of Fe3+ back to Fe2+, which in turn will catalyze the formation of highly reactive oxidants from H2O2
  • Depending on concentrations, the effects of ascorbate on models of lipid peroxidation can be pro- or antioxidant
  • Nathan Goodyear on 07 Jul 19
     
    ferritin released enhanced pharmacologic ascorbate induced-cytotoxicity, indicating that ferritin with high iron-saturation could be a source of catalytic iron. Consistent with this, ascorbate has also been shown to be capable of releasing iron from cellular ferritin
Nathan Goodyear

The Role of Vitamin C in Human Immunity and Its Treatment Potential Against COVID-19: A... - 0 views

www.ncbi.nlm.nih.gov/...PMC9925039

COVID-19 SARS-CoV-2 COVID WBC ascorbic acid vitamin C

shared by Nathan Goodyear on 01 Sep 23 - No Cached
  • vitamins A, B, C, E, B6, B12, folate, zinc, iron, copper, and selenium
  • White blood cells, including neutrophils and monocytes, accumulate concentrations of vitamin C up to 100 times greater than that of plasma
  • Vitamin C is a crucial component of both the innate (nonspecific) and adaptive (specific) portions of the immune system
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  • play a role during the initial chemotactic response of neutrophils shortly after infection
  • following vitamin C supplementation, a 20% increase in neutrophil chemotactic activity was observed
  • also contributes to the phagocytosis and killing of microbes by neutrophils
  • low levels of vitamin C occurring in high-stress situations
  • maturation, proliferation, and viability of T cells have all been shown to be upregulated by the presence of normal physiologic concentrations of vitamin C
  • Vitamin C has been shown to directly affect the number of Igs released from B cells
  • vitamin C among healthy young adult males showed a significant increase in serum levels of IgA, IgG, and IgM
  • effects of high-dose vitamin C on cytokine levels in cancer patients, finding decreased amounts of the cytokines Interleukin-1 alpha (IL-1 alpha), IL-2, IL-8, and tumor necrosis factor-alpha (TNF-alpha) after high-dose vitamin C infusion
  • when vitamin C was supplemented with vitamin E in healthy adults, it increased the production of cytokines IL-1 beta and TNF-alpha
  • vitamin C acts to modulate the levels of cytokines to prevent them from fluctuating in either direction
  • vitamin C also acts as an important antioxidant to the cells of the immune system.
  • human leukocytes, neutrophils, in particular, possess the ability to transport the oxidized form of vitamin C across its membrane to use as a defense mechanism against ROS produced during an immune response
  • Vitamin C also can recover other endogenous antioxidants in the body such as vitamin E and glutathione, returning them to their active state
  • vitamin C can decrease the activation of NF-kB
  • can reduce harmful nitrogen-based compounds such as N-nitrosamines and nitrosamides, both of which are carcinogenic 
  • subjects taking oral vitamin C supplementation saw a 60% to 90% reduction in oxidative stress compared to a placebo control
  • subjects infused with vitamin C alone had a 516% increase in glutathione levels compared to subjects not provided the 500 mg daily supplementation
  • hydroxylating proline and lysine
  • mature and stabilize the tissue of a healing wound
  • healing
  • oral surgery
  • improved soft tissue regeneration
  • vitamin C increases the mRNA levels of type I and type III collagen in the human dermis
  • Studies have demonstrated that those with low levels of vitamin C are at a significantly higher risk of respiratory infection compared to those with normal levels
  • viral cold duration was reduced by about 8% in adults and 13.5% in children using prophylactic daily doses of 200 mg of oral vitamin C
  • prophylactically supplementing vitamin C decreases the risk of infection with respiratory viruses such as the common cold
  • combined with probiotics, oral vitamin C supplementation showed a 33% decrease in the incidence of respiratory tract infections in preschool-age children [
  • high-dose oral supplementation of vitamin C managed to prevent or reduce symptoms if taken before or just after the onset of cold- or flu-like symptoms
  • improvements in oxygen saturation and decreased IL-6 levels (a marker of inflammation) in the treatment group compared to the control group
  • 8 g doses of oral vitamin C
  • there is a negative correlation between age and serum levels of vitamin C
  • Patients with COVID-19 will likely also experience depletion in serum levels of vitamin C as a direct result of the upregulation of the immune system to combat the infection
  • Colunga et al. suggested that oral vitamin C can be combined with oral Quercetin, an antiviral flavonoid, to improve Quercetin’s ability to block viral membrane fusion of SARS-CoV-2
  • high doses of 1-2 g/day of oral vitamin C could prevent other upper respiratory infections
  • It appears vitamin C supplementation by itself does not provide a striking benefit in preventing COVID-19 infection for those without a deficiency
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Flawed statement. What is normal? Vitamin D. Many variables effect levels and dose, including the two compartment kinetics and absorption.
  • Hiedra et al. were able to show decreases in inflammatory biomarkers, such as D-dimer and ferritin
  • some evidence to support that prophylactic use of vitamin C helps reduce the severity of respiratory infection symptoms once a subject has already been infected
  • oral vitamin C in combination with zinc provided the largest amount of antibody titers 42 days
  • linear relationship between days of vitamin C therapy and survival duration
  • other studies were unable to find any definitive improvement concerning therapy with vitamin C
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Either these studies are designed to fail or the authors are lacking some basic understanding of pharmacokinetics and pharmacodynamics with vitamin C.
  • Fowler et al. aimed to see if a high-dose vitamin C infusion would benefit patients affected by ARDS, but they were unable to conclude that vitamin C infusion, compared to a placebo, could decrease vascular inflammation and damage in ARDS
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      At what dose, duration, frequency???
  • in a sample of 67 COVID-19-positive ICU patients, 82% of them displayed plasma vitamin C levels below 0.4 mg/dL
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      They are kind of make the point from my earlier note.
  • continuous vitamin C infusion at a rate of 60 mg/kg/day for four days decreased the need for mechanical ventilation and vasopressor use but had no significant effect on overall mortality
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      Again, designed to fail or ignorance designed the study which failed
  • Carr et al. suggested that high-dose IV vitamin C is most effective when treating sepsis as septic patients receiving the normal daily recommendations through diet still showed decreased vitamin C levels
  • High-dose IV vitamin C treatment has also been shown by Kakodkar et al. to decrease syndecan-1, an endothelial glycocalyx that contributes to mortality in septic patients
  • combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure
  • combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure
  • reduced overall mortality
  • reduced overall mortality
  • propose the use for high-dose vitamin C to aid in the treatment of septic shock-induced hypotension
  • treatment of severe sepsis using a high dose (up to 200 mg/kg/day) of IV vitamin C was explored in phase I, a double-blind, randomized, placebo-controlled trial by Fowler et al. [75]. Their findings included a reduction in SOFA scores and decreased vascular injury compared to a placebo control group, all while showing minimal adverse side effects
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      High dose here is laughable. Again, duration and frequency also.
  • Maintaining a daily intake of 75 and 100 mg for men and women, respectively, as recommended by the U.S. Institute of Medicine
    • Nathan Goodyear
      Nathan Goodyear on 01 Sep 23
       
      This recommendation is FRANK IGNORANCE
Nathan Goodyear

Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis - 1 views

www.ncbi.nlm.nih.gov/...PMC3937164

sepsis IV vitamin C vitamin C CRP

shared by Nathan Goodyear on 11 Oct 17 - No Cached
  • Padayatty and colleagues showed that high-level ascorbic acid plasma concentrations could only be achieved by intravenous administration
  • No patient in the low or high dose ascorbic acid treatment arms of this study suffered any identifiable adverse event
  • a pharmacologic ascorbic acid treatment strategy in critically ill patients with severe sepsis appears to be safe
  • ...7 more annotations...
  • subnormal plasma ascorbic acid levels are a predictable feature in patients with severe sepsis
  • Ascorbic acid depletion in sepsis results from ascorbic acid consumption by the reduction of plasma free iron, ascorbic acid consumption by the scavenging of aqueous free radicals (peroxyl radicals), and by the destruction of the oxidized form of ascorbic acid dehydroascorbic acid
  • Sepsis further inhibits intracellular reduction of dehydroascorbic acid, producing acute intracellular ascorbic acid depletion
  • Ascorbic acid treated patients in this study exhibited rapid and sustained increases in plasma ascorbic acid levels using an intermittent every six hours administration protocol
  • Septic ascorbic acid-deficient neutrophils fail to undergo normal apoptosis. Rather, they undergo necrosis thereby releasing hydrolytic enzymes in tissue beds, thus contributing to organ injury
  • We speculate that intravenous ascorbic acid acts to restore neutrophil ascorbic acid levels
  • Repletion of ascorbic acid in this way allows for normal apoptosis, thus, preventing the release of organ damaging hydrolytic enzymes.
  • Nathan Goodyear on 11 Oct 17
     
    Study finds IV vitamin C in patients with sepsis is very safe and blunts the effects (endothelial damage, end organ damage...) of sepsis.  Of note, the IV vitamin C group reached serum levels of ascorbic acid of 1,592 to 5,722 micromol/L.  The IV groups maintained elevated serum C levels for up to 96 hours post infusion.  
Nathan Goodyear

Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and h... - 0 views

www.ncbi.nlm.nih.gov/...PMC1885574

vitamin C ascorbic acid Cancer

shared by Nathan Goodyear on 05 Mar 18 - No Cached
  • Proposed mechanism
  • The data show that pharmacologic ascorbate concentrations produced Asc•− selectively in extracellular fluid compared with blood and that H2O2 formation occurred when Asc•− concentrations were >100 nM in extracellular fluid.
  • These data validate the hypothesis that ascorbate is a prodrug for selective delivery of reactive species to the extravascular space
  • ...22 more annotations...
  • pharmacologic ascorbate as a prooxidant drug for therapeutic use.
  • Recently we reported that pharmacologic ascorbic acid concentrations produced H2O2 concentrations of ≥25 μM, causing cancer cell death in vitro
  • We found that H2O2 concentrations generated in vivo were those that caused cancer cell death in vitro
  • When ascorbate was given parenterally, Asc•−, the product of a loss of one electron from ascorbate, was detected preferentially in extracellular fluid compared with blood
  • Asc•− generation in extracellular fluid depended on the ascorbate dose and the resulting concentrations
  • With i.v. administration of ascorbate, Asc•− concentrations were as much as 12-fold greater in extracellular fluid compared to blood and approached 250 nM
  • In blood, such Asc•− concentrations were never produced and were always <50 nM
  • These data are all consistent with the hypothesis that pharmacologic ascorbate concentrations in vivo serve as a prodrug for selective delivery of H2O2 to the extracellular space
  • After oral ingestion, control of intracellular and extracellular ascorbate concentrations is mediated by three mechanisms: intestinal absorption, tissue transport, and renal reabsorption
  • intestinal absorption, or bioavailability, declines at doses >200 mg
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      significant limitation of gut absorption of vitamin C--at 200 mg po.
  • corresponding to plasma concentrations of ≈60 μM
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      equates to 0.06 mM.  Max blood levels found with po AA dosing has been 0.22 mM
  • at approximately this concentration, the ascorbate tissue transporter SVCT2 approaches Vmax, and tissues appear to be saturated
    • Nathan Goodyear
      Nathan Goodyear on 05 Mar 18
       
      SVCT2 Rc in gut reach max binding.
  • also at ≈60 μM, renal reabsorption approaches saturation, and excess ascorbate is excreted in urine
  • Parenteral administration bypasses tight control
  • When tight control is bypassed, H2O2 forms in the extracellular space
  • in vivo validation of ascorbate as a prodrug for selective H2O2 formation
  • Temporarily bypassing tight control with parenteral administration of ascorbate allows H2O2 to form in discrete time periods only, decreasing likelihood of harm, and provides a pharmacologic basis for therapeutic use of i.v. ascorbate
  • H2O2 formation results in selective cytotoxicity
  • Tumor cells are killed with exposure to H2O2 for ≤30 min
  • In vitro, killing is mediated by H2O2 rather than Asc•−
  • In addition to cancer treatment, another potential therapeutic use is for treatment of infections. H2O2 concentrations of 25–50 μM are bacteriostatic
  • virally infected cells may also be candidates
  • Nathan Goodyear on 05 Mar 18
     
    follow up invivo study to previous study from 2005.  Here, the authors prove their hypothesis that ascorbate is a prodrug for delivery of H2O2.
Nathan Goodyear

From the Cover: Pharmacologic doses of ascorbate act as a prooxidant and decrease growt... - 0 views

www.ncbi.nlm.nih.gov/...PMC2516281

cancer IV intravenous vitamin C IV vitamin C

shared by Nathan Goodyear on 18 Sep 13 - No Cached
  • An extensive panel of 43 tumor and 5 normal cell lines were exposed to ascorbate in vitro for ≤2 h to mimic clinical pharmacokinetics
  • effective concentration that decreased survival 50% (EC50) was determined. EC50 was <10 mM for 75% of tumor cells tested, whereas cytotoxicity was not evident in normal cells with >20 mM ascorbate
  • The addition of catalase to the medium ameliorated death of ovarian carcinoma (Ovcar5), pancreatic carcinoma (Pan02), and glioblastoma (9L) cells exposed to 10 mM ascorbate (1 h), indicating cytotoxicity was mediated by H2O2
  • ...8 more annotations...
  • A treatment dose of 4 g ascorbate/kg body weight either once or twice daily did not produce any discernible adverse effects
  • Xenograft experiments showed that parenteral ascorbate as the only treatment significantly decreased both tumor growth and weight by 41–53%
  • Peak plasma concentrations of ascorbate approached 30 mM
  • Pharmacologic concentrations of ascorbate decreased tumor volumes 41–53% in diverse cancer types known for both their aggressive growth and limited treatment options.
  • Our findings showed that pharmacologic ascorbic acid concentrations were cytotoxic to many types of cancer cells in vitro (Fig. 1A) and significantly impeded tumor progression in vivo without toxicity to normal tissues
  • The amelioration of ascorbate cytotoxicity in vitro by the addition of catalase was consistent among sensitive cancer cells (Fig. 1B) and points unambiguously to H2O2 generation in the extracellular medium
  • the current in vivo data support that pharmacologic ascorbate concentrations, which can readily be achieved in humans (Fig. 3E), diminished growth of several aggressive cancer types in mice (Fig. 2) without causing apparent adverse effects.
  • These intratumoral H2O2 concentrations of >125 μM persisted for >3 h after ascorbate administration
  • Nathan Goodyear on 18 Sep 13
     
    Tumor xenograft model in mice finds reduction in growth rates of ovarian cancer, pancreatic cancer, and glioblastoma with daily IV vitamin C.
Nathan Goodyear

Oncotarget | NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Id... - 0 views

www.oncotarget.com/index.php

vitamin C IV vitamin C cancer cancer stem cells milk thistle silymarin ascorbic acid bee propolis CAPE glycolytic inhibitor natural

shared by Nathan Goodyear on 08 Dec 17 - No Cached
  • Vitamin C was ~10 times more potent than 2-DG for the targeting of CSCs
  • Cancer stem-like cells (CSCs) are thought to be the root cause of chemotherapy-resistance and radio-resistance
  • ultimately leading to treatment failure in patients with advanced disease [1-3]. They have been directly implicated mechanistically in tumor recurrence and metastasis, resulting in poor patient survival
  • ...26 more annotations...
  • mitochondrial biogenesis may be a key driver of the CSC phenotype
  • Our results indicate that increased mitochondrial oxidative stress and high NADH levels are both key characteristics of the CSC metabolic phenotype
  • high levels of NAD(P)H auto-fluorescence are known to be a surrogate marker for mitochondrial “power”, high OXPHOS capacity and increased ATP production
  • CSCs may be strictly dependent on NAD(P)H to maintain their enhanced mitochondrial function
  • an intact NAD+ salvage pathway is strictly required for mammosphere formation, supporting our results using NAD(P)H auto-fluorescence, which enriched CSC activity by more than 5-fold.
  • Since glycolysis is especially critical for maintaining the TCA cycle, OXPHOS and overall mitochondrial function, we next assessed the effects of known glycolytic inhibitors
  • we show that two other natural products that function as effective glycolysis inhibitors, also inhibited mammosphere formation. More specifically, vitamin C (ascorbic acid), which induces oxidative stress and inhibits the activity of GAPDH (a key glycolytic enzyme) [17], also inhibited mammosphere formation, with an IC-50 of 1 mM (Figure 7B). Therefore, vitamin C was ~10 times more potent than 2-DG at targeting CSC propagation
  • silibinin (the major active constituent of silymarin, an extract of milk thistle seeds) [18], which specifically functions as an inhibitor of glucose uptake, blocked mammosphere formation, with an IC-50 between 200 and 400 µM
  • caffeic acid phenyl ester (CAPE), a key component of honey-bee propolis, has potent anti-cancer properties
  • Propolis has a strong history of medicinal use, dating back more than 2,000 years
  • Because of it aromatic ring structure (Figure 8), we speculated that CAPE might function as a potent inhibitor of oxidative mitochondrial metabolism
  • CAPE quantitatively inhibits the mitochondrial oxygen consumption rate (OCR) and, in turn, induces the onset of aerobic glycolysis (ECAR)
  • CAPE shows a clear selectivity for targeting CSCs and adherent cancer cells, relative to normal fibroblasts.
  • CAPE functions as a “natural” mitochondrial OXPHOS inhibitor, that preferentially targets the CSC sub-population. This could explain CAPE’s known anti-cancer properties
  • Our data directly shows that a small fraction of the total cell population, characterized by increased PGC1α activity, high mitochondrial ROS/H2O2 and high NADH levels, has the ability to survive and grow under anchorage-independent conditions, driving mammosphere formation
  • We highlight the utility of certain natural products, such as Silibinin, Vitamin C and CAPE, that could be used to therapeutically target CSCs. Silibinin is the major active component of silymarin, which is an extract prepared from milk thistle seeds.
  • high NADH is a property that is conserved between normal and cancerous stem cells
  • Previous studies have also shown that when non-CSCs and CSCs are both fed mitochondrial fuels (such as L-lactate or ketone bodies), that CSCs quantitatively produce more NADH in response to this stimulus
  • CSCs may be strictly dependent on NADH to maintain their enhanced mitochondrial function
  • The Noble Prize winner, Linus Pauling, was among the first to describe and clinically test the efficacy of Vitamin C, as a relatively non-toxic anti-cancer agent
  • Vitamin C has two mechanisms of action. First, it is a potent pro-oxidant, that actively depletes the reduced glutathione pool, leading to cellular oxidative stress and apoptosis in cancer cells. Moreover, it also behaves as an inhibitor of glycolysis, by targeting the activity of GAPDH, a key glycolytic enzyme.
  • Here, we show that Vitamin C can also be used to target the CSC population, as it is an inhibitor of energy metabolism that feeds into the mitochondrial TCA cycle and OXPHOS
  • Vitamin C may prove to be promising agent for new clinical trials, aimed at testing its ability to reduce CSC activity in cancer patients, as an add-on to more conventional therapies, to prevent tumor recurrence, further disease progression and metastasis
  • Interestingly, a breast cancer based clinical study has already shown that the use of Vitamin C, concurrent with or within 6 months of chemotherapy, significantly reduces both tumor recurrence and patient mortality
  • CAPE quantitatively reduces mitochondrial oxygen consumption (OCR), while inducing a reactive increase in glycolysis (ECAR). As such, it potently inhibits mammosphere formation with an IC-50 of ~2.5 µM. Similarly, it also significantly inhibits cell migration
  • we also demonstrate that 7 different inhibitors of key energetic pathways can be used to effectively block CSC propagation, including three natural products (silibinin, ascorbic acid and CAPE). Future studies will be necessary to test their potential for clinical benefit in cancer patients.
  • Nathan Goodyear on 08 Dec 17
     
    The future of cancer therapy is cancer stem cells.  Study finds that Vitamin C, silymarin, and bee propolis blocks mitochondrial energy pathways in cancer stem cells.  Vitamin C is a known glycolytic inhbitor. Vitamin C was found to inhibit glycolysis via GAPDH targeting to inhibit the energy pathways of the mitochondria in CSCs.  The authors propse that Vitamin C can be used as add on therapies for conventional therapies to specifically attack the CSCs and their contribution to recrurence, treatment resistance, and metastasis potential all in addition to the ability of vitamin C to reduce the side effects of chemotherapy.
fitspresso

https://www.sightcare-co.com/ - 0 views

www.sightcare-co.com

sight care sightcare group training nearsightedness food for eyesight carey codd vitasight vision how to cure bad eye tips fix improve your red light eyes diet improvement skincare malaysia costos de medicare indonesia singapore eyecare

shared by fitspresso on 27 Sep 23 - No Cached
  • fitspresso on 27 Sep 23
     
    Sight Care | Official Site sightcare-co.com · by Sight Care Sight Care Only $49/Bottle Limited Time Offer! Sight Care Special Deal + Special 67% Discount Save $600 + 180 Days Money Back Guarantee #1.The Sight Care vision supplement is a dietary supplement for helping you improve your vision and brain health. Sight Care eye supplements are formulated to provide a synergistic blend of vitamins, minerals, antioxidants, and other bioactive compounds that are essential for maintaining healthy vision Regular Price: 147/per bottle Only for: $49/per bottle What Is Sight Care? This powerful vision support supplement is made with a unique blend of natural ingredients and plant extracts that work together synergistically to deliver numerous benefits for your brain and eye health. With Sight Care, you can expect to experience increased energy levels, improved eyesight, and an overall revitalized sense of well-being. Taking care of your vision health is not just about seeing clearly; it's also about maintaining your overall brain health. As we age, our vision deteriorates, and our eyes and brain can experience a decline in function, but there are steps you can take to support your visual and cognitive health. Regular eye exams are crucial for detecting and treating vision problems early on, and making healthy choices such as eating a nutritious diet and exercising regularly can also help. However, with busy schedules, it can be difficult to find the time to devote to a healthy lifestyle. This is where the Sight Care supplement comes in. It's designed to support both vision and brain health with its blend of natural ingredients that have been shown to promote healthy vision and cognitive function You must not compromise your eye health for momentary exhilaration. If you are glued to digital screens day and night, you must take measures to prevent eye diseases like age-related macular degeneration. The SightCare vision supplement has been made using 100% natura
Nathan Goodyear

Increased Tumor Ascorbate is Associated with Extended Disease-Free Survival and Decreas... - 0 views

www.ncbi.nlm.nih.gov/...PMC3912592

hypoxia HIF-1 IV vitamin C VEGF Hypoxia-inducible Factor 1 vitamin C HIF-1alpha cancer

shared by Nathan Goodyear on 02 Apr 21 - No Cached
  • Nathan Goodyear on 02 Apr 21
     
    Enough said: "There was an inverse relationship between tumor ascorbate content and HIF-1 pathway activation and tumor size. Higher tumor ascorbate content was associated with significantly improved disease-free survival in the first 6 years after surgery with additional disease-free days. This was independent of tumor grade and stage. Survival advantage was associated with the amount of ascorbate in the tumor, but not with the amount in adjacent normal tissue. Our results demonstrate that higher tumor ascorbate content is associated with decreased HIF-1 activation."
Nathan Goodyear

Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic... - 0 views

www.ebiomedicine.com/...fulltext

multiple myeloma vitamin C IV vitamin C smoldering myeloma cancer

shared by Nathan Goodyear on 25 Sep 17 - No Cached
  • Recent reports indicate that a certain ROS concentration is required for high-dose vitamin C to induce cytotoxicity in cancer cells.
  • The generation of ascorbyl- and H2O2 radicals by PAA increases ROS stress in cancer cells
  • In this study, we report that PAA is efficacious in killing MM cells in vitro and in vivo models, which generated levels of 20–40 mM ascorbate and 500 nM ascorbyl radicals after intraperitoneal administration of 4 g ascorbate per kilogram of body weight (Chen et al., 2008Chen et al., 2008), in xenograft MM mice
  • ...33 more annotations...
  • These data suggest that PAA may show a therapeutic advantage to blood cancers vs solid tumors because of the communication between tumor cells and blood plasma
  • These results strongly suggest that the mechanism of PAA killing of MM cells is indeed iron-dependent
  • These results suggest that PAA administration in SMM may be able to prevent progression to symtomatic MM
  • A recent study by Yun and colleagues demonstrated that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, but spares normal cells
  • RAS family genes show the most frequent mutations in MM. KRAS, NRAS and BRAF are mutated in 22%, 20% and 7% of MM samples
  • the disease stage rather than the mutation of RAS and/or BRAF is the major predictive factor for PAA sensitivity in MM treatment
  • Other molecular mechanisms including ATP depletion and ATM-AMPK signaling have been reported to explain PAA-induced cell death
  • our pilot study also suggested that PAA could overcome drug resistance to bortezomib in MM cells
  • Our findings complement reported studies and further address the mechanism of action using clinical samples in which we observed that PAA killed tumor cells with high iron content, suggesting that iron might be the initiator of PAA cytotoxicity
  • combination of PAA with standard therapeutic drugs, such as melphalan, may significantly reduce the dose of melphalan needed
  • Combined treatment of reduced dose melphalan with PAA achieved a significantly longer progression-free survival than the same dose of melphalan alone.
  • These data also suggest that the bone marrow suppression induced by high-dose melphalan can be ameliorated by the combination of PAA with lower dose of melphalan because of the lack of toxicity of PAA on normal cells with low iron content.
  • if creatinine clearance is <30 mL/min, high dose ascorbic acid should be not administrated.
  • In MM preclinical and clinical studies, ascorbate was used as an adjunct drug and showed controversial results (Harvey et al., 2009, Perrone et al., 2009, Held et al., 2013, Sharma et al., 2012, Nakano et al., 2011, Takahashi, 2010, Sharma et al., 2009, Qazilbash et al., 2008). However, none of these tests used pharmacological doses of ascorbate and intravenous administration
  • Multiple myeloma (MM) is a plasma cell neoplasm.
  • Cameron and Pauling reported that high doses of vitamin C increased survival of patients with cancer
  • pharmacologically dosed ascorbic acid (PAA) 50–100 g (Chen et al., 2008, Padayatty et al., 2004, Hoffer et al., 2008, Padayatty et al., 2006, Welsh et al., 2013), administered intravenously, has potent anti-cancer activity and its role as anti-cancer therapy is being studied at the University of Iowa and in other centers
  • In the presence of catalytic metal ions like iron, PAA administered intravenously exerts pro-oxidant effects leading to the formation of highly reactive oxygen species (ROS), resulting in cell death
  • the labile iron pool (LIP) is significantly elevated in MM cells
  • The survival of CD138+ cells in vitro was significantly decreased following PAA treatment in all 9 MM
  • In contrast, no significant change of cell viability was observed in CD138− BM cells from the same patients
  • The same effect of PAA was also observed in the SMM patients
  • no response to PAA was detected in CD138+ cells from the 2 MGUS patients
  • the combination of melphalan plus PAA showed greater tumor burden reduction than each drug alone, suggesting a synergistic activity between these two drugs
  • Both catalase and NAC protect cells from oxidative damage
  • cells pretreated with NAC and catalase became resistant to PAA even at high doses
  • adding deferoxamine (DFO), an iron chelator, to OCI-MY5 cells before PAA treatment was also sufficient to prevent PAA-induced cellular death
  • iron is essential for PAA to achieve its anti-cancer activity
  • PAA induced early necrosis (Fig. 3Fig. 3A, 60 min) followed by late apoptosis
  • results further indicated that PAA induced mitochondria-mediated apoptosis
  • PAA by reacting with LIP and generating ROS induces mitochondria-mediated apoptosis in which AIF1 cleavage is important for cell death.
  • ROS and H2O2 are well known factors mediating PAA-induced cancer cell death
  • PAA was sensitive to all 9 MMs and 2 SMMs
  • Nathan Goodyear on 25 Sep 17
     
    animal study finds high-dose, pharmacologic vitamin C found to kill multiple myeloma cells via pro-oxidant effect found in similar studies in dealing with different cancers.
Nathan Goodyear

Intravenously administered vitamin C as cancer therapy: three cases - 0 views

www.ncbi.nlm.nih.gov/...PMC1405876

IV vitamin C vitamin C cancer

shared by Nathan Goodyear on 24 Apr 17 - No Cached
  • peak plasma concentrations obtained intravenously are estimated to reach 14 000 μmol/L, and concentrations above 2000 μmol/L may persist for several hours
  • Emerging in vitro data show that extracellular ascorbic acid selectively kills some cancer but no normal cells by generating hydrogen peroxide
  • Death is mediated exclusively by extracellular ascorbate, at pharmacologic concentrations that can be achieved only by intravenous administration
  • ...6 more annotations...
  • Vitamin C may serve as a pro-drug for hydrogen peroxide delivery to extravascular tissues, but without the presence of hydrogen peroxide in blood
  • not all cancer cells were killed by ascorbic acid in vitro
  • Intravascular hemolysis was reported after massive vitamin C administration in people with glucose-6-phosphate dehydrogenase deficiency
  • Administration of high-dose vitamin C to patients with systemic iron overload may increase iron absorption and represents a contraindication
  • Ascorbic acid is metabolized to oxalate, and 2 cases of acute oxalate nephropathy were reported in patients with pre-existing renal insufficiency given massive intravenous doses of vitamin C
  • Rare cases of acute tumour hemorrhage and necrosis were reported in patients with advanced cancer within a few days of starting high-dose intravenous vitamin C therapy, although this was not independently verified by pathologic review
  • Nathan Goodyear on 24 Apr 17
     
    IV vitamin C associated with prolonged survival in 3 patients with different cancers.  Peak serum levels reached 14,000 micromol/L, which levels above the 1,000 micro mol/L (cancer cell cytotoxic threshold) were maintained for hours
Nathan Goodyear

Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2... - 0 views

www.nature.com/...s41698-017-0044-8

cancer cancer stem cells liver cancer vitamin C IV vitamin C oncology

shared by Nathan Goodyear on 30 Jan 18 - No Cached
  • Chen et al. have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.
  • Ascorbic acid (the reduced form of vitamin C) is specifically transported into cells by sodium-dependent vitamin C transporters (SVCTs)
  • SVCT-1 is predominantly expressed in epithelial tissues
  • ...41 more annotations...
  • whereas the expression of SVCT-2 is ubiquitous
  • differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.
  • high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.
  • Hepatocellular carcinoma (HCC)
  • The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells
  • DNA double-strand damage was found following VC treatment
  • DNA damage was prevented by NAC
  • Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight
  • Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs
  • VC is one of the numerous common hepatoprotectants.
  • Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells
  • we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.
  • Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients
  • Median DFS time for VC users was 25.2 vs. 18 months for VC non-users
  • intravenous VC use is linked to improved DFS in HCC patients.
  • In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      the authors here made similar mistakes to the Mayo authors i.e. under doses here in this study.  They dosed at only 2 grams IVC.  A woefully low dose of IVC.
  • Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      positive results despite a low dose used.
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      Their comfort zone was 1mM.  They should have targeted 20-40 mM.
  • Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy
  • As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity
  • we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs
  • SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC
  • CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance
  • we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death
  • as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs
  • In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells
  • we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo
  • Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      so, exclude the benefit to patients until the exact mechanism of action, which will never be fully elicited?!?!?
  • Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy
    • Nathan Goodyear
      Nathan Goodyear on 31 Jan 18
       
      Terribly inadequate dose.  Target is 20-40 mM which other studies have found occur with 50-75 grams of IVC.
  • several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS
  • high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo
  • high recurrence rate and heterogeneity
  • tumor progression, metastasis, and chemotherapy-resistance
  • SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues
  • high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior
  • SVCT-2 is enriched in liver CSCs
  • these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.
  • pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration
  • The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner
  • VC and cisplatin combination further caused cell apoptosis in tumor xenograft
  • These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response
  • qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs
  • Nathan Goodyear on 30 Jan 18
     
    IV vitamin C in vitro and in vivo found to "preferentially" eradicate cancer stem cells.  In addition, IV vitamin C was found to be adjunctive to chemotherapy, found to be hepatoprotectant.  This study also looked at SVCT-2, which is the transport protein important in liver C uptake.
Nathan Goodyear

O2*− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Su... - 0 views

www.ncbi.nlm.nih.gov/...PMC5497844

Cancer "vitamin C" "IV vitamin H2O2 Fe ascorbate ascorbic acid redox

shared by Nathan Goodyear on 04 Dec 18 - No Cached
  • Nathan Goodyear on 04 Dec 18
     
    Great read and synopsis of the interaction between vitamin C and the altered redox balance in cancer cells. The process involves Fe in part. Ascorbate increases H2O2 which increases the label Fe pool.
Nathan Goodyear

Pharmacological ascorbate induces cytotoxic... [Anticancer Drugs. 2012] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...22205155

vitamin C vitamin C cancer prostate cancer prostate IV vitamin C intravenous vitamin C IV intravenous ascorbic acid

shared by Nathan Goodyear on 26 Aug 14 - No Cached
  • Nathan Goodyear on 26 Aug 14
     
    IV vitamin C induces cell death of prostate cancer cell lines via H2O2, which is not new, but what is new is the ascorbate-insensitive cell line.
Nathan Goodyear

Vitamin C and cancer revisited - 0 views

www.ncbi.nlm.nih.gov/...PMC2516245

IV vitamin C cancer vitamin C H2O2 hydrogen peroxide Fe

shared by Nathan Goodyear on 05 Mar 18 - No Cached
  • It is well known that vitamin C, or ascorbic acid, is an effective biologic antioxidant and does not act as a pro-oxidant under normal conditions (5) because it does not readily autoxidize, i.e., react with oxygen (O2) to produce reactive oxygen species, such as superoxide radicals (O2•−) or H2O2
  • However, ascorbate readily donates an electron to redox-active transition metal ions, such as cupric (Cu2+) or ferric (Fe3+) ions, reducing them to cuprous (Cu+) and ferrous (Fe2+) ions, respectively
  • Reduced transition metal ions, in contrast to ascorbic acid, readily react with O2, reducing it to superoxide radicals (Reaction 2), which in turn dismutate to form H2O2 and O2
  • ...6 more annotations...
  • The H2O2 produced this way (Reactions 1–3) seems to be key to ascorbate's antitumor effect because H2O2 causes cancer cells to undergo apoptosis, pyknosis, and necrosis
  • In contrast, normal cells are considerably less vulnerable to H2O2
  • The reason for the increased sensitivity of tumor cells to H2O2 is not clear but may be due to lower antioxidant defenses
  • In fact, a lower capacity to destroy H2O2—e.g., by catalase, peroxiredoxins, and GSH peroxidases—may cause tumor cells to grow and proliferate more rapidly than normal cells in response to low concentrations of H2O2
  • These observations, combined with the inhibitory effect on xenograft growth, provide the proof of concept that millimolar concentrations of extracellular ascorbate, achievable by i.p. injection or i.v. infusion in experimental animals and humans, respectively, exert pro-oxidant, antitumor effects in vivo.
  • They also show that the concentration of the ascorbyl radical correlates with the concentration of H2O2 in interstitial fluid, whereas no H2O2 can be detected in blood or plasma
  • Nathan Goodyear on 05 Mar 18
     
    review of the mechanism of how extracellular AA, only obtainable from parenteral dosing, can produce H2O2 extracellularly to then be cytotoxic to cancer cells.
Nathan Goodyear

The role of vitamin C in the treatment of pain: new insights - 0 views

www.ncbi.nlm.nih.gov/...PMC5391567

vitamin C pain arthritis

shared by Nathan Goodyear on 18 Sep 17 - No Cached
  • recommended that during illness one should be careful about the intake of vitamin C, keeping in mind that acute illness rapidly depletes stores of ascorbic acid
  • it is possible that other hospital-associated pain may be partly due to vitamin C deficiency, which is relatively prevalent in hospital settings
  • Vitamin C deficiency (defined as plasma vitamin C concentrations <11 µmol/L
  • ...5 more annotations...
  • Vitamin C is cost effective and appears to be a safe and effective adjunctive therapy for specific pain relief
  • it decreases the requirement for opioid analgesics, particularly post surgically and for bone metastasis
  • recent research has indicated a positive impact of high dose vitamin C on cancer- and chemotherapy-related quality of life, including pain
  • Cameron and Campbell [81] reported a number of cases of dramatic to complete amelioration of bone pain in patients with severe cancer-related pain given both high dose oral and intravenous vitamin C
  • hypovitaminosis C (defined as plasma vitamin C concentrations <23 µmol/L
  • Nathan Goodyear on 18 Sep 17
     
    vitamin C reduces pain; mechanism of action likely anti-inflammatory antioxidant, but yet inconclusive.
Nathan Goodyear

Nutrients | Free Full-Text | Myths, Artifacts, and Fatal Flaws: Identifying Limitations... - 0 views

www.mdpi.com/...htm

vitamin C ascorbic acid

shared by Nathan Goodyear on 24 Sep 18 - No Cached
  • l-gulonolactone oxidase, an enzyme with the synthesis of l-ascorbic acid as its only known function
  • prolonged fasting causes ascorbate synthesis to decline
  • agents that stimulate glycogenolysis also stimulate ascorbate synthesis when an animal is in a fed state
  • Nathan Goodyear on 24 Sep 18
     
    Great review on the science of vitamin C.
Nathan Goodyear

Effect of high dose intravenous ascorbic acid on the level of inflammation in patients ... - 0 views

www.riordanclinic.org/...MRI-v01n02-p26.pdf

RA rheumatoid arthritis rheumatoid arthritis IV vitamin C intravenous IV vitamin C ascorbic vitamin C inflammation autoimmune

shared by Nathan Goodyear on 10 Dec 12 - No Cached
  • Nathan Goodyear on 10 Dec 12
     
    This study, small pilot, showed that they were able to lower inflammation in those suffering from RA, through high dose vitamin C IV therapy. This study stopped at 25 gms. The vitamin C is a scavenger of ROS and ROS stimulates inflammation through NF-kappaB. This is how vitamin C can reduce inflammation.
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