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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

Molecules | Free Full-Text | Silymarin/Silybin and Chronic Liver Disease: A Marriage of... - 0 views

www.mdpi.com/...htm

silymarin milk thistle liver disease cirrhosis detoxification natural therapy alternative medicine

shared by Nathan Goodyear on 13 Mar 17 - No Cached
  • Nathan Goodyear on 13 Mar 17
     
    Good review of the literature on Silymarin, from Milk Thistle, and liver disease.
Nathan Goodyear

Inhibition of human carcinoma cell growth and DNA ... [Cancer Lett. 1999] - PubMed result - 0 views

www.ncbi.nlm.nih.gov/...10660092

milk thistle silymarin prostate cervical breast cancer inhibition anti-cancer

shared by Nathan Goodyear on 15 Feb 11 - No Cached
  • Several studies from our laboratory have shown the cancer chemopreventive and anti-carcinogenic effects of silymarin, a flavonoid antioxidant isolated from milk thistle, in long-term tumorigenesis models and in human prostate, breast and cervical carcinoma cells
  • Nathan Goodyear on 15 Feb 11
     
    milk thistle shows anti-cancer effect in prostate, breast, and cervical cancers
Nathan Goodyear

The Long-term Survival of a Patient With Pancreatic Cancer With Metastases to the Liver... - 0 views

LDN pancreatic cancer low dose naltrexone alpha lipoic acid cancer

shared by Nathan Goodyear on 07 Jul 19 - No Cached
  • Nathan Goodyear on 07 Jul 19
     
    Interesting case study: also included po Se, ALA, silymarin, and B vits.
Nathan Goodyear

Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type... - 0 views

edrv.endojournals.org/...599.long

free radicals oxidative stress damage inflammation type II DM alpha lipoic acid alpha-lipoic-acid diabetes

shared by Nathan Goodyear on 02 Aug 12 - No Cached
  • In patients with diabetes, LA levels are reduced (48, 74, 103). LA has long been used for the treatment of diabetic neuropathy in Germany
  • evidence indicates that it increases insulin sensitivity in patients with type 2 diabetes
  • LA has been shown to 1) quench free radicals, 2) prevent singlet oxygen-induced DNA damage, 3) exhibit chelating activity, 4) reduce lipid peroxidation, 5) increase intracellular glutathione levels, and 6) prevent glycation of serum albumin (73, 74). LA is able to reduce oxidative stress-mediated NF-κB activation in vitro (74, 108, 109) and in patients with type 2 diabetes
  • ...2 more annotations...
  • Activation of NF-κB can also be blocked by several other thiol-containing antioxidants including N-acetyl-l-cysteine (NAC)
  • Other clinically available antioxidants reported to have antiinflammatory, antioncogenic, and/or antiatherogenic properties that have been shown to block the activation of NF-κB include resveratrol (115, 116), (-)-epicatechin-3-gallate (117), pycnogenol (118), silymarin (119), and curcumin (120)
  • Nathan Goodyear on 02 Aug 12
     
    Great read!  If you want to see how free radicals and oxidative stress contribute to inflammation and disease (DM in this case), read this article.
Nathan Goodyear

http://lipoic.dreamhosters.com/berkson/1999-Berkson-Med-Klin.pdf - 0 views

lipoic.dreamhosters.com/...1999-Berkson-Med-Klin.pdf

alpha lipoic acid milk thistle silymarin selenium hepatitis liver disease damage

shared by Nathan Goodyear on 10 Feb 14 - No Cached
  • Nathan Goodyear on 10 Feb 14
     
    Triple antioxidant therapy in the treatment of Hepatitis C.
Nathan Goodyear

http://www.integratedhealthclinic.com/assets/byCancerType/Pancreatic/4-LDN%20and%20IV%2... - 0 views

www.integratedhealthclinic.com/...IV%20Alpha%20Lipoic%20Acid.pdf

alpha lipoic acid ALA cancer pancreatic LDN low dose naltrexone selenium milk thistle silymarin IV intravenous

shared by Nathan Goodyear on 10 Feb 14 - No Cached
  • Nathan Goodyear on 10 Feb 14
     
    Author describes the long-term survival of a man with metastatic pancreatic cancer using IV alpha lipoic acid, low dose naltrexone, diet, and oral triple therapy of milk thistle, ALA, and selenium.  The safety profile is very good as compared to traditional therapy for metastatic pancreatic cancer.
Nathan Goodyear

A conservative triple antioxidant approach to the treatment of hepatitis C. Combination... - 0 views

www.ncbi.nlm.nih.gov/...10554539

alpha lipoic acid milk thistle selenium hepatitis C liver disease

shared by Nathan Goodyear on 20 May 15 - No Cached
  • Nathan Goodyear on 20 May 15
     
    Alpha lipoic acid, milk thistle, and selenium found useful in 3 case studies with hepatitis C.  Only abstract available here.
Nathan Goodyear

Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis ... - 0 views

www.ncbi.nlm.nih.gov/...22797645

milk thistle hepatitis C hepatitis liver disease HCV

shared by Nathan Goodyear on 20 May 15 - No Cached
  • Nathan Goodyear on 20 May 15
     
    study finds milk thistle unsuccessful in lower ALT in HCV patients that had failed interferon therapy.  The dosing used in this study was low.
Nathan Goodyear

Broad targeting of angiogenesis for cancer prevention and therapy - 0 views

www.ncbi.nlm.nih.gov/...PMC4737670

cancer curcumin VEGF EGCG green tea melatonin quercetin Resveratrol silymarin flavonoids HIF-1alpha

shared by Nathan Goodyear on 01 Jun 18 - No Cached
  • vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), interleukin-8 (IL-8), placental growth factor (PlGF), transforming growth factor-beta (TGFbeta), platelet derived growth factor (PDGF), angiopoietins (Angs) and others (reviewed in [4])
  • The switch may also involve down-regulation of endogenous inhibitors of angiogenesis such as endostatin, angiostatin or thrombospondin (reviewed in [5]) and has thus been regarded as the result of tipping the net balance between positive and negative regulators
  • There is a complex interrelationship between tumor hypoxia and tumor angiogenesis
  • ...17 more annotations...
  • chronic hypoxia
  • acute hypoxia
  • Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth
  • HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)
  • When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways
  • c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.
  • mTOR can also promote stabilization and HIF transcriptional activity
  • hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment
  • Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration
  • Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments
  • The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group
  • Resveratrol inhibits capillary endothelial cell growth and new blood vessel growth in animals
  • interrupting cell proliferation, inducing apoptosis
  • [155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha
  • resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha
  • prevents cytokine-induced vascular leakage and tumor metastasis
  • The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors
  • Nathan Goodyear on 01 Jun 18
     
    natural compounds to attach cancer explained.
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