both 2- and 4-catechol estrogen metabolites bind to the ER with affinities comparable
with estradiol, 4-catechol estrogen metabolites have lower dissociation rates than estradiol and an enhanced ability to upregulate
ER-dependent processes
Group items tagged
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Peroxisome Proliferator-activated Receptor α Activation Modulates Cellular Re... - 0 views
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DHEA inhibits NF-kappaB stimulated TNF-alpha production through regulation of PPAR-alpha.
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Urinary Estrogens and Estrogen Metabolites and Subsequent Risk of Breast Cancer among P... - 0 views
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estrogen metabolites estrogen metabolism ER estrogen receptors ROS hormones cancer breast cancer
shared by Nathan Goodyear on 07 Oct 15
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2-catechol estrogen metabolites act as either weak mitogens (39) or weak inhibitors of cell proliferation
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While 16α-hydroxyestrone binds to the ER with lower affinity than estradiol, it binds covalently (41) and leads to a constitutively activated ER
- ...15 more annotations...
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4-hydroxyestradiol and 16α-hydroxyestrone increasing proliferation and decreasing apoptosis in a manner similar to estradiol; however, these effects were achieved only at concentrations 10-fold higher than estradiol (39). In contrast, 2-hydroxyestradiol did not have substantial proliferative or antiapoptotic effects
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In our study, the associations with both 2-hydroxyestrone and 16α-hydroxyestrone were nonsignificantly inverse and we did not observe a consistent trend or significant associations between the 2-hydroxyestrone:16α-hydroxyestrone ratio and breast cancer risk
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Ratios of the 3 hydroxylation pathways were not significantly associated with risk although the 2:16-pathway and 4:16-pathway ratios were suggestively inversely associated
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a significant inverse association with the ratio of parent estrogens to estrogen metabolites
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several potentially estrogenic and genotoxic mechanisms
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Estrogen metabolites also can be genotoxic
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Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly via redox cycling and generation of reactive oxygen species
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the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized 2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination and mutations
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2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative DNA damage
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act independently from the ER
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16α-Hydroxyestrone also may be genotoxic
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While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol estrogens with one hydroxyl group methylated, have been hypothesized to lower the risk of breast cancer
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The suggested mechanisms are indirect, by decreasing circulating levels of catechol estrogens and thereby the opportunity for catechols to exert genotoxic or proliferative effects, or direct, by inhibiting tumor growth and inducing apoptosis
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the balance between phase I (oxidation) and phase II (methylation) metabolism of estrogen may be important in hormonally related cancer development.
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Despite the estrogenic and genotoxic potential of many of the estrogen metabolites, we only observed a significantly increased breast cancer risk with one estrogen metabolite, 17-epiestriol, which has particularly strong estrogenic activity and binds to both ERα and ERβ with an affinity comparable with estradiol
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review of estrogen metabolites and breast cancer risk in premenopausal women.
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Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among p... - 0 views
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While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol estrogens with one hydroxyl group methylated, have been hypothesized to lower risk of breast cancer.
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Despite the estrogenic and genotoxic potential of many of the EM, we only observed a significantly increased breast cancer risk with one EM, 17-epiestriol, which has particularly strong estrogenic activity and binds to both ERα and ERβ with an affinity comparable to estradiol
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We did not observe reduced risk for higher concentrations of 2-pathway EM relative to 16-pathway EM, nor did we observe a consistent benefit of higher concentrations of methylated catechol EM compared with catechol EM.
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EM also can be genotoxic, but the individual EM vary in their ability to induce DNA damage
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Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly via redox cycling and generation of reactive oxygen species
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the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized 2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination and mutations
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2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative DNA damage (46). These catechols also induce neoplastic transformation in ER-cells, and thus act independently from the ER
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Testosterone regulation of homocysteine metabolism modulates redox status in human pros... - 0 views
www.ncbi.nlm.nih.gov/...17854288
Testosterone homoecysteine glutathione prostate cancer cancer male hormones
shared by Nathan Goodyear on 22 Jun 15
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in disease prostate, Testosterone down regulates transulfuration pathway and glutathione production.
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Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in c... - 0 views
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Active Vitamin B12 and Folate treatment benefits some children with autism spectrum disorders
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Metabolic biomarkers of increased oxidative stress... [Am J Clin Nutr. 2004] - PubMed r... - 0 views
www.ncbi.nlm.nih.gov/...15585776
ASD autism spectrum disorder detoxification children SAMe SAH homocysteine cystathionine glutathione adenosine
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children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione
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This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism
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increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
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detoxification impairment and the markers to assess it in children with ASD
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How environmental and genetic factors combine to c... [Neurotoxicology. 2008] - PubMed ... - 0 views
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Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects.
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a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.
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Medical ozone increases methotrexate clinical response and improves cellular redox bala... - 0 views
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Growth Inhibition of Ovarian Tumor-Initiating Cells by Niclosamide | Molecular Cancer T... - 0 views
mct.aacrjournals.org/...1703.long
Niclosamide Tumor-initiation cells TIC ovarian cancer cancer CSC cancer stem cells
shared by Nathan Goodyear on 16 Apr 18
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Ovarian cancer is the most lethal gynecologic malignancy and the fifth-most cause of overall cancer death of women in developed countries
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An increasingly accepted cancer stem cell hypothesis regards tumors as caricatures of normal organs, possessing a hierarchy of cell types, at various stages of aberrant differentiation, descended from precursor tumor-initiating cells (TIC) cells that are highly resistant to conventional cytotoxics
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Significant changes of gene expression in 2,928 genes were identified after niclosamide treatment for different time periods
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uncoupling of mitochondrial oxidative phosphorylation is believed to be its anti-helminthic mechanism of action
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we hypothesized that niclosamides antagonistic effects on OTICs could, in part, be due to its disruption of metabolism
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Our results showed that genes participating in protein complexes of oxidative phosphorylation were downregulated
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niclosamide treatment resulted in a more than 20% increase in reactive oxygen species (ROS) in cultured OTICs
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niclosamide, which has proved to be safe and effective for the past 2 decades against numerous parasites, inhibited OTIC growth both in vitro and in vivo
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niclosamide represses metabolic enzymes responsible for bioenergetics, biosynthesis, and redox regulation specifically in OTICs, presumably leading to mitochondrial intrinsic apoptosis pathways, loss of tumor stemness, and growth inhibition
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Niclosamide is believed to inhibit mitochondrial oxidative phosphorylation
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Niclosamide was reported to inactivate NF-κB, causing mitochondrial damage and the generation of ROS, leading to apoptosis of leukemic stem cells
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niclosamide were identified in a screen for mTOR-signaling inhibitors
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mTOR was reported to maintain stemness properties of HSCs by inhibiting mitochondrial biogenesis and ROS levels (39), implying that mTOR inhibitors (such as niclosamide) may interfere with mitochondria and various metabolic pathways in TICs via disruption of antioxidant responses
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We observed Wnt hyperactivity in OTICs, in agreement with previous hypotheses of Wnt inhibitor effectiveness as an ovarian cancer therapy
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niclosamide has now been independently identified in screens for Wnt inhibitors
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downregulation of the Wnt/β-catenin target oncogenes survivin and c-Myc
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ovarian carcinogenesis, the cell-to-cell signaling pathway Notch (8), were also suppressed by niclosamide (data not shown). These results agree with another recent niclosamide study in leukemia (49), and it has been widely hypothesized that disruption of Notch signaling may represent a highly effective therapy for ovarian and other solid tumors, via its essentiality to maintaining TIC stemness
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Niclosamide, common anti-parasitic medication, inhibits cellular metabolism and increases ROS; both of which provide powerful anti-proliferative, anti-cancer treatment mechanism in TICs. Powerful target therapy for cancer stem cells. Also shown to inhibit Wnt stimulated oncogenes survivin and c-Myc, disrupts Notch signaling, inactivates NF-kappaBeta, and inhibits mTOR-signaling. This has been found in in vitro and in vivo studies.
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The rate of cellular hydrogen peroxide removal shows dependency on GSH: Mathematical in... - 0 views
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High levels of ROS will lead to a more oxidized redox environment thereby inducing cell damage or even cell death
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Catalase
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six members of the peroxiredoxin family of enzymes
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glutathione peroxidases
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all reduce H2O2 to water (organic hydroperoxides are reduced to water and the corresponding alcohol) with the electrons coming from GSH, a necessary and specific cofactor.
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good review of the interaction between H202 and the glutathione pathway. This has significant implications in the mechanism of action in cancer cells with IV vitamin C.
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Vitamin C and cancer revisited - 0 views
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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
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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
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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
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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
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In contrast, normal cells are considerably less vulnerable to H2O2
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The reason for the increased sensitivity of tumor cells to H2O2 is not clear but may be due to lower antioxidant defenses
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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
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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.
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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
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review of the mechanism of how extracellular AA, only obtainable from parenteral dosing, can produce H2O2 extracellularly to then be cytotoxic to cancer cells.
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Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views
nutritionandmetabolism.biomedcentral.com/...s12986-017-0178-2
ketogenic diet ketogenic press-pulse hyperbaric oxygen therapy HBOTnutrition diet cancer HBOT IVC IV vitamin C DCA dichloracetic acid cancer therapy cancer treatment alternative cancer treatment
shared by Nathan Goodyear on 09 Jul 17
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mamdouh_hfz liked it
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A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
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“pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
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Neoplasia involving dysregulated cell growth is the biological endpoint of the disease
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Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
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cancer is predicted to overtake heart disease as the leading cause of death in Western societies
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cancer can also be recognized as a metabolic disease.
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glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
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Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
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persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
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Otto Warburg first proposed that all cancers arise from damage to cellular respiration
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The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
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the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
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The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
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Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
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Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
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all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
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The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
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respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
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data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
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Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
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In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival
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Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
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Glucose and glutamine act synergistically for driving rapid tumor cell growth
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Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions
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Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
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Hif-1α stabilization enhances aerobic fermentation
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targeting glucose and glutamine will deprive the microenvironment of fermentable fuels
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Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
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Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
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Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
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Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
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Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
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It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
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Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
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The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
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According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
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A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
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Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
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Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
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The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
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Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
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reason to eliminate glutamine in cancer patients and even GSH with cancer patients
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It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
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Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
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glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
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In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
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Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
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Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
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Ketone bodies and fats are non-fermentable fuels
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Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
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Apoptosis under energy stress is greater in tumor cells than in normal cells
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A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
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. This energy stress acts as a press disturbance
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Drugs that target availability of glucose and glutamine would act as pulse disturbances
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Hyperbaric oxygen therapy can also be considered another pulse disturbance
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The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
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Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
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Protein amino acids can be metabolized to glucose through the Cori cycle
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The fats in KDs used clinically also contain more medium chain triglycerides
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Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
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Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
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GKI values of 1.0 or below are considered therapeutic
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The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
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It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
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The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
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Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
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Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
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Ketones are much more than energy adaptabilit, but actually are therapeutic.
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ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
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Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
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Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
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In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
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Ketone supplementation has also been shown to reduce anxiety behavior in animal models
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This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
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lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
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Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
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A synergistic interaction of the KD diet plus radiation was seen
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It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
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Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
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HBOT also increases oxidative stress and membrane lipid peroxidation of GBM cells in vitro
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The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
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Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
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Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
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Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
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GBM and use glutamine as a major fuel
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Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
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Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
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Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
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Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
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Cancer is a mitochondrial disease? So says the well published Dr Seyfried. Glucose and glutamine drive cancer growth.
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Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation - ScienceDi... - 0 views
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Low dose radiation from CT found to contribute to altered genetic expression of p53 tumor suppressor gene to give competitive advantage to potential cancer cells over health cells.
24More
Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde... - 0 views
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Hydroxyl radicals cause oxidative damage to cells because they unspecifically attack biomolecules [22] located less than a few nanometres from its site of generation and are involved in cellular disorders such as neurodegeneration [23, 24], cardiovascular disease [25], and cancer [26, 27].
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It is generally assumed that in biological systems is formed through redox cycling by Fenton reaction, where free iron (Fe2+) reacts with hydrogen peroxide (H2O2) and the Haber-Weiss reaction that results in the production of Fe2+ when superoxide reacts with ferric iron (Fe3+)
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other transition-metal including Cu, Ni, Co, and V can be responsible for formation in living cells
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The hydroperoxyl radical () plays an important role in the chemistry of lipid peroxidation
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The is a much stronger oxidant than superoxide anion-radical
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Lipid peroxidation can be described generally as a process under which oxidants such as free radicals or nonradical species attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs) that involve hydrogen abstraction from a carbon, with oxygen insertion resulting in lipid peroxyl radicals and hydroperoxides as described previously
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under medium or high lipid peroxidation rates (toxic conditions) the extent of oxidative damage overwhelms repair capacity, and the cells induce apoptosis or necrosis programmed cell death
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The overall process of lipid peroxidation consists of three steps: initiation, propagation, and termination
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Once lipid peroxidation is initiated, a propagation of chain reactions will take place until termination products are produced.
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The main primary products of lipid peroxidation are lipid hydroperoxides (LOOH)
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Among the many different aldehydes which can be formed as secondary products during lipid peroxidation, malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal (4-HNE) have been extensively studied
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MDA has been widely used for many years as a convenient biomarker for lipid peroxidation of omega-3 and omega-6 fatty acids because of its facile reaction with thiobarbituric acid (TBA)
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MDA is one of the most popular and reliable markers that determine oxidative stress in clinical situations [53], and due to MDA’s high reactivity and toxicity underlying the fact that this molecule is very relevant to biomedical research community
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4-HNE is considered as “second toxic messengers of free radicals,” and also as “one of the most physiologically active lipid peroxides,” “one of major generators of oxidative stress,” “a chemotactic aldehydic end-product of lipid peroxidation,” and a “major lipid peroxidation product”
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MDA is an end-product generated by decomposition of arachidonic acid and larger PUFAs
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Identifying in vivo MDA production and its role in biology is important as indicated by the extensive literature on the compound (over 15 800 articles in the PubMed database using the keyword “malondialdehyde lipid peroxidation” in December 2013)
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MDA reactivity is pH-dependent
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When pH decreases MDA exists as beta-hydroxyacrolein and its reactivity increases
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MAA adducts are shown to be highly immunogenic [177–181]. MDA adducts are biologically important because they can participate in secondary deleterious reactions (e.g., crosslinking) by promoting intramolecular or intermolecular protein/DNA crosslinking that may induce profound alteration in the biochemical properties of biomolecules and accumulate during aging and in chronic diseases
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MDA is an important contributor to DNA damage and mutation
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This MDA-induced DNA alteration may contribute significantly to cancer and other genetic diseases.
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Dietary intake of certain antioxidants such as vitamins was associated with reduced levels of markers of DNA oxidation (M1dG and 8-oxodG) measured in peripheral white blood cells of healthy subjects, which could contribute to the protective role of vitamins on cancer risk
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4-HNE is an extraordinarily reactive compound
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New promising developments for potential therapeutic applications of high-dose ascorbat... - 0 views
www.sciencedirect.com/...S1658387620301746
vitamin C HIF-1 SVCT hypoxia redox GLUT cancer fenton reaction HIF-1alpha
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Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 0 views
www.ncbi.nlm.nih.gov/...PMC5282724
EMT TME metastasis cancer stem cells cancer MMP2 Notch MMP-9 MMP-2 radioresistance Hedgehog CSC MMP9 Snail HIF-1alpha tumor microenvironment epithelial to mesenchymal transition TGF-beta radiation
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More than half of cancer patients are treated with IR at some point during their treatment
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fractionation schedule is the delivery of 1.8–2.0 Gy per day, five days per week
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Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
- ...121 more annotations...
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IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production
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IR is known to induce EMT in vitro
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p53 is activated in response to IR-induced DNA damage
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IR paradoxically also promotes tumour recurrence and metastasis
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DNA double-strand breaks (DSBs)
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cancer cells undergoing EMT acquire invasive and metastatic properties
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changes in the tumour microenvironment (TME)
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IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism
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EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
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Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
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EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
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IR is known to induce stemness and metabolic alterations in cancer cells
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transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
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activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
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Loss of E-cadherin is considered a hallmark of EMT
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IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
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IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
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sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
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ROS are known to play an important role in IR-induced EMT
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High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
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hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT
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Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
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Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion
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IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
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NF-κB signalling that promotes cell migration
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ROS promote EMT to allow cancer cells to avoid hostile environments
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HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
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Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
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levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
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IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
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IR induces vascular damage that causes hypoxia
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ROS is implicated in IR-induced HIF-1 activation
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IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
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IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
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The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
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TGF-β signalling has been shown to play a crucial role in IR-induced EMT
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AP-1 transcription factor is involved in IR-induced TGF-β1 expression
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Wnt/β-catenin signalling is also implicated in IR-induced EMT
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Notch signalling is known to be involved in IR-induced EMT
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IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail
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PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
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EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
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ROS and RNS are also implicated in IR-induced EGFR activation
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IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT
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IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
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CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
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Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
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identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
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CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
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Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,
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signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
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microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451
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Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes
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EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
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Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
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TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
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some CSC subpopulations arise independently of EMT
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IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
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Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
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IR has been shown to induce reprogramming of differentiated cancer cells into CSCs
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In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
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IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
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EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
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STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
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Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
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metabolic reprogramming
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HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
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metabolic reprogramming
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tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis
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occurring within the same tumour
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CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen
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mitochondrial function is crucial for maintaining CSC functionality
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cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
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HIF-1 then enhances glycolysis
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CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
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lactate transporter, monocarboxylate transporter (MCT)
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nutrient microenvironment
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Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
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MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
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metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
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bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
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the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
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HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
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regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
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HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
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HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
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STAT3 has been implicated in EMT-induced metabolic changes as well
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TGF-β and Wnt play important roles in the metabolic alteration of cancer cells
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Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness
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EMT, invasion, metastasis, and stemness
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pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
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decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis
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LDH catalyses the bidirectional conversion of lactate to pyruvate
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High levels of LDHA are positively correlated with the expression of EMT and CSC markers
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IR has been shown to induce metabolic changes in cancer cells
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
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IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
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Lactate can activate latent TGF-
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lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
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promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
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tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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intrinsic immunogenicity or induce tolerance
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cancer immunoediting’
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three phases: 1) elimination, 2) equilibrium, and 3) escape.
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The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
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IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
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IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
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TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
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MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
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IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis
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IR-induced Snail increases MMP-2 expression to promote EMT
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Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness
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IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
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Metabolic alterations
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oncogenic metabolism
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elicit various changes in the TME
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Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
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