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High-dose ascorbate infusion makes cancer treatment more effective, trial shows

High-dose ascorbate infusion makes cancer treatment more effective, trial shows. … a brain storming session … by Ladislav Šoltés. noxa/noxae. Cells standard standard. cancer cell. Solid tumors https://www.slideshare.net/assr9/common-pediatric-solid-tumors.

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High-dose ascorbate infusion makes cancer treatment more effective, trial shows

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  1. High-dose ascorbate infusion makes cancer treatment more effective,trial shows … a brain storming session … by Ladislav Šoltés Medical News Today 3/31/2017

  2. noxa/noxae Cells standard standard cancer cell L. Šoltés

  3. Solid tumorshttps://www.slideshare.net/assr9/common-pediatric-solid-tumors L. Šoltés

  4. Solid tumorshttps://www.slideshare.net/assr9/common-pediatric-solid-tumors L. Šoltés

  5. Solid tumorshttps://www.slideshare.net/assr9/common-pediatric-solid-tumors L. Šoltés

  6. Solid tumorshttps://www.slideshare.net/assr9/common-pediatric-solid-tumors L. Šoltés

  7. High-dose ascorbate infusionhttps://www.sciencedaily.com/releases/2017/03/170330142341.htm Altered iron metabolism in cancer cells, and not normal cells, lead to increased sensitivity to cancer cell killing caused by high dose vitamin C The patients received three infusions of vitamin C a week for 2 months followed by two infusions per week for 7 months while receiving standard care radiation and chemotherapy. The goal of each infusion was to raise the concentration of vitamin C in a patient's blood to 20,000 μmol/l, as compared to a blood level of about 70 μmol/l found in most adults. The high dose is necessary because vitamin C has a half-life of about 2 hours in the circulation of humans. The tumor tissue contains high level of redox active iron molecules (a by-product of abnormal mitochondrial metabolism), which react with vitamin C to form H2O2 and free radicals derived from H2O2. These free radicals are believed to cause DNA damage selectively in cancer cells (vs. normal cells) leading to enhanced cancer cell death. L. Šoltés

  8. Cellsstandard cancer L. Šoltés

  9. Cancer cell death Cellsstandard cancer Cancer Cell 31 (2017) 487–500http://www.sciencedirect.com/science/article/pii/S1535610817300624?via%3Dihub L. Šoltés

  10. Cellsstandard cancer Otázky na autorov Cancer Cell 31 (2017) 487–500 ? O ktorom „transitional metal“ ióne uvažujete v extracelulárnom priestore ? ? ? V intracelulárnom priestore sú prítomné aj ióny Cu2+ ! ? ? ? Viete o tom, že koncentrácia GSH v nádorových bunkách je omnoho vyššia ako v bunkách štandardných ? ? ? ?Produkcia H2O2 mitochondriami je zanedbateľná. Energiu nádorová bunka tvorí glykolýzou ! ?Je v cytosole nádorových buniek molekulový kyslík, alebo bunka je v podmienkach hypoxie ? Cancer Cell 31 (2017) 487–500http://www.sciencedirect.com/science/article/pii/S1535610817300624?via%3Dihub L. Šoltés

  11. Major biogenic elements (6) • Carbon(C) • Hydrogen(H) • Oxygen(O) • Nitrogen(N) • Sulfur(S) • Phosphorus(P) Carbohydrates Lipids Proteins Enzymes DNA 3 4 5 6 L. Šoltés

  12. ! DNA je maximálne chránená pred poškodením • Koncentrácia GSH v cytosole !!! Cellsstandard cancer Koncentrácia GSH v bunkách štandardných 10000 μmol/l, v nádorových >> 10000 μmol/l. L. Šoltés

  13. Cellsstandard cancer To achieve the 20,000 μmol/lconcentration of vitamin C in a patient's blood (5 liters in total) that means injection of “a bolus” of 17.6 g of vitamin C ! A slow infusion application means> >> > >17.6 g !!! L. Šoltés

  14. … a tissue …standard cancer L. Šoltés

  15. Carbohydrates: standard … 3% cancer … >>>3% … details of the cell surface …standard cancer Extracellular fluid nm Cytosol 1/4/2020 15 L. Šoltés L. Šoltés

  16. Major biogenic elements (6) • Carbon(C) • Hydrogen(H) • Oxygen(O) • Nitrogen(N) • Sulfur(S) • Phosphorus(P) Carbohydrates Lipids Proteins Enzymes DNA 3 4 5 6 L. Šoltés

  17. Carbohydrates: standard … 3% cancer … >>>3% … details of the cell surface …standard cancer Extracellular fluid nm Cytosol 1/4/2020 17 L. Šoltés L. Šoltés

  18. … Glycocalyx functions … standard • Has a negative electrical charge which attracts positively charged ions • Protect cells against damages • Serve to attach cells to one another • Act as a part of the receptor sites • Enter into immune reactions 1/4/2020 L. Šoltés 18

  19. of lower-molar-masses stimulates immunity responses immunogenic Immunogenic carbohydrates immunogenic … Glycocalyx functions … cancer 1/4/2020 L. Šoltés 19

  20. Cellsstandard cancer Otázky na autorov Cancer Cell 31 (2017) 487–500 ? O ktorom „transitional metal“ ióne uvažujete v extracelulárnom priestore ? • Manganese (Mn) +2, +7, +6, +4, +3 • Iron (Fe) +3, +2, +5 , (+4), (+6) • Cobalt (Co) +2, +3 , +4 • Copper (Cu) +2, +1 • Zinc (Zn)+2 • Vanadium (V) +5, +2, +3, +4 • Molybdenum (Mo)+6, +2, +3, +4, +5 • Nickel (Ni) +2, +3 ? Hadi S.M. et al., Chemotherapy 56 (2010) 280–284 “Catalytic Therapy of Cancer by Ascorbic Acid Involves Redox Cycling of Exogenous/Endogenous Copper Ions and Generation of Reactive Oxygen Species” L. Šoltés

  21. Cu(I)---complex + [Fe(III)---complex] → H+ + [Fe(II)---complex] + + [Fe(III)---complex] → [Fe(II)---complex] + DHA t1/2 = 10-9 s; site specific .OH generation !!! Involvement of transition metals Fe Cu [Fe(II)---complex] + O2→ [Fe(III)---complex] + O2.- 2O2.- + 2H+ → H2O2 + O2 ......dismutation reaction H2O2+[Fe(II)---complex]→ .OH + [Fe(III)---complex] + HO- AscH- + 2[Fe(III)---complex] → H+ + 2[Fe(II)---complex] + DHA Dismutation reactions are usually very slow H2O2 + Cu(I)---complex→.OH +Cu(II) Weissberger A. et al., Oxidation processes. XVI. The autoxidation of ascorbic acid.J Amer Chem Soc1943, 65, 1934–1939 L. Šoltés

  22. Cu(I)---complex t1/2 = 10-9; site specific .OH generation !!! Ergothioneine = (+)-charged thiol H2O2 + Cu(I)---complex→.OH +Cu(II) L. Šoltés

  23. reduktívna chelatácia Cu(II) + ES-→ Cu(I) + ½ESSE Cu(I) + ES-→ ES---Cu(I) __________________________________________ 1Cu(II) + 2ES-→ ES---Cu(I) + ½ESSE Motohashi N. et al., Complexing of cooper ion by ergothionenine. Chem Pharm Bull1976, 24, 2364–2368 Reduction of cupric to cuprous ion by thiol P. Rapta, K. Valachová, I. Valent, L. Šoltés

  24. Cu(II) Cu(II) Cu(II) … Glycocalyx functions … cancer Thiol application 1/4/2020 L. Šoltés 24

  25. Cu(I) Cu(I) Cu(I) … Glycocalyx functions … cancer H2O2 action 1/4/2020 L. Šoltés 25

  26. .OH .OH .OH … Glycocalyx functions … cancer 1/4/2020 L. Šoltés 26

  27. .OH Hyaluronan (HA) fragmentation + Initiation: HA + •OH→ A• + H2O L. Šoltés

  28. Hyaluronan fragmentation HA fragments → immuno-stimulatory L. Šoltés

  29. of lower-molar-masses stimulates immunity responses immunogenic Immunogenic carbohydrates immunogenic … Glycocalyx functions … cancer treatment 1/4/2020 L. Šoltés 29

  30. … how to “demask” a tumor … • High-molar-mass hyaluronan solution with addition of Cu(II) ions • Ascorbic acid was added 1 h later (black curve) K. Valachová

  31. … how to “demask” a tumor … • High-molar/mass hyaluronan solution with addition of Cu(II) ions = time zero • Ascorbic acid was added 1 h later (black curve) • Ergothioneine applied = time zero [Cu(II):ergothioneine=1:2] • Ascorbic acid was added 1 h later (yellow curve) K. Valachová

  32. … how to “demask” a tumor … • High-molar/mass hyaluronan solution with addition of Cu(II) ions = time zero • Ascorbic acid was added 1 h later (black curve) Ergothioneine applied = time zero [Cu(II):ergothioneine=1:2] • Ascorbic acid was added 1 h later (yellow curve) • High-molar/mass hyaluronan solution with addition of Cu(II) ions and ergothioneine = time zero • ½ Ascorbic acid was added 1 h later (blue curve) K. Valachová

  33. .OH … Conclusions … ... „treatment“ ... Is it based on targeting DNA by .OH ? Cancer Cell 31 (2017) 487–500http://www.sciencedirect.com/science/article/pii/S1535610817300624?via%3Dihub L. Šoltés

  34. .OH .OH … Conclusions … ... „treatment“ ... Is it a demasking the cells by .OH ? Our TEAM: Hypotesis, speculation L. Šoltés et al.

  35. .OH .OH … Conclusions … ... „treatment“ ... Is it a demasking the cells by .OH ? ... „treatment“ ... Infusion of a thiol prior Asc-would potentiate the action of even lower ascorbate dose ? Our TEAM: Hypotesis, speculation L. Šoltés et al.

  36. … Conclusions … L. Šoltés

  37. … Conclusions … K. Valachová et al.

  38. Nature 551, 37–382 November 2017 The surprising history of an antioxidant L. Šoltés

  39. Acknowledgements MA Jardine LPKhonde 1/4/2020 39 The TEAM

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