High-Dose Vitamin C for Cancer Therapy - PMC - 0 views
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diabetes [8], atherosclerosis [9], the common cold [10], cataracts [11], glaucoma [12], macular degeneration [13], stroke [14], heart disease [15], COVID-19 [16], and cancer.
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1–5% of the Vit-C inside the human cells
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interaction between Fe(II) and H2O2 produces OH− through the Fenton reaction
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metabolic activity, oxygen transport, and DNA synthesis
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Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.
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macrophages contain considerable quantities of iron
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iron is taken up by the majority of cells in the form of a transferrin (Tf)-Fe(III) complex that binds to the cell surface receptor transferrin receptor 1 (TfR1)
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excess iron is retained in the liver cells
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the endosomal six transmembrane epithelial antigen of the prostate 3 (STEAP3) reduces Fe(III) (ferric ion) to Fe(II) (ferrous ion), which is subsequently transferred across the endosomal membrane by divalent metal transporter 1 (DMT1)
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labile iron pool (LIP)
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LIP is toxic to the cells owing to the production of massive amounts of ROS.
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DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH
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Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)
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Ascorbate can efficiently reduce free iron, thus recycling the cellular Fe(II)/Fe(III) to produce more OH• from H2O2 than can be generated during the Fenton reaction, which ultimately leads to lipid, protein, and DNA oxidation
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Vit-C-stimulated iron absorption
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reduce cellular iron efflux
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high-dose Vit-C may elevate cellular LIP concentrations
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ascorbate enhanced cancer cell LIP specifically by generating H2O2
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Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately
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tumor cells have a need for readily available Fe(II) to survive and proliferate.
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Tf has been recognized to sequester most labile Fe(II) in vivo
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Asc•− and H2O2 were generated in vivo upon i.v Vit-C administration of around 0.5 g/kg of body weight and that the generation was Vit-C-dose reliant
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free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production
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iron metabolism is altered in malignancies
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increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways
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Fe(II) ion in breast cancer cells is almost double that in normal breast tissues
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macrophages in the cancer microenvironment have been revealed to increase iron shedding
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Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease
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increased the amount of LIP inside the cells through transferrin receptor (TfR)
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Warburg effect, or metabolic reprogramming,
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Warburg effect is aided by KRAS or BRAF mutations
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Vit-C is supplied, it oxidizes to DHA, and then is readily transported by GLUT-1 in mutant cells of KRAS or BRAF competing with glucose [46]. DHA is quickly converted into ascorbate inside the cell by NADPH and GSH [46,107]. This decrease reduces the concentration of cytosolic antioxidants and raises the intracellular ROS amounts
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increased ROS inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
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ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+ (a critical co-factor of GAPDH); thus, further reducing the GAPDH associated with a multifaceted metabolic rewiring
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Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
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high-dose Vit-C recruited metabolites and increased the enzymatic activity in the pentose phosphate pathway (PPP), blocked the tri-carboxylic acid (TCA) cycle, and increased oxygen uptake, disrupting the intracellular metabolic balance and resulting in irreversible cell death, due to an energy crisis
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mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2
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Due to its great volatility at neutral pH [76], bolus therapy with mega-dose DHA has only transitory effects on tumor cells, both in vitro and in vivo.