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Nathan Goodyear

Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological... - 0 views

www.ncbi.nlm.nih.gov/...PMC5106370

cancer IV vitamin C vitamin c catalase

shared by Nathan Goodyear on 30 Jan 18 - No Cached
  • Nathan Goodyear on 30 Jan 18
     
    Cancer cells have reduced catalase activity and thus reduced capability to metabolize H202. IV vitamin takes advantage of this deficiency.
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

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.
Nathan Goodyear

Combined treatment with vitamin C and methotrexate inhibits triple-negative breast canc... - 0 views

www.spandidos-publications.com/...or.2017.5439

IV vitamin C breast cancer EGFR triple negative breast cancer vitamin C TNBC Caspase-3 methotrexate

shared by Nathan Goodyear on 15 Mar 21 - No Cached
  • Nathan Goodyear on 15 Mar 21
     
    Low dose methotrexate + low dose vitamin C inhibit TNBC via EGFR mechanism
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
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  • 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.
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