1. … a brain storming session … by Ladislav Šoltés
11/23/2018
High-dose ascorbate infusion makes cancer treatment more effective, trial shows
… a brain storming session …
by Ladislav Šoltés
11/23/2018
Medical News Today 3/31/2017

2. Cells standard standard
cancer cell
noxa/noxae
11/23/2018
L. Šoltés

3. Solid tumors https://www. slideshare
11/23/2018
L. Šoltés

4. Solid tumors https://www. slideshare
11/23/2018
L. Šoltés

5. Solid tumors https://www. slideshare
11/23/2018
L. Šoltés

6. Solid tumors https://www. slideshare
11/23/2018
L. Šoltés

7. High-dose ascorbate infusion https://www. sciencedaily
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.
11/23/2018
L. Šoltés

8. Cells standard cancer
11/23/2018
L. Šoltés

9. Cells standard cancer Cancer cell death 11/23/2018 L. Šoltés

10. Cells standard 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) 487–500
11/23/2018
L. Šoltés

11. Major biogenic elements (6)
11/23/2018
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
11/23/2018
L. Šoltés

12. Cells standard cancer Koncentrácia GSH v cytosole !!!
! DNA je maximálne chránená pred poškodením
Koncentrácia GSH v cytosole !!!
Koncentrácia GSH v bunkách štandardných μmol/l, v nádorových >> μmol/l.
11/23/2018
L. Šoltés

13. Cells standard cancer
To achieve the 20,000 μmol/l concentration 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 !!!
11/23/2018
L. Šoltés

14. … a tissue … standard cancer
11/23/2018
L. Šoltés

15. … details of the cell surface … standard cancer
Extracellular fluid
Carbohydrates:
standard … 3%
cancer … >>> 3% nm
Cytosol
11/23/2018
11/23/2018
L. Šoltés
L. Šoltés 15

16. Major biogenic elements (6)
11/23/2018
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
11/23/2018
L. Šoltés

17. … details of the cell surface … standard cancer
Extracellular fluid
Carbohydrates:
standard … 3%
cancer … >>> 3% nm
Cytosol
11/23/2018
11/23/2018
L. Šoltés
L. Šoltés 17

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
11/23/2018
11/23/2018
L. Šoltés 18

19. of lower-molar-masses stimulates immunity responses
… Glycocalyx functions … cancer
of lower-molar-masses
stimulates immunity responses
Immunogenic
carbohydrates
immunogenic
11/23/2018
11/23/2018
L. Šoltés 19

20. Cells standard cancer Otázky na autorov Cancer Cell 31 (2017) 487–500
? O ktorom „transitional metal“ ióne uvažujete
v extracelulárnom priestore ?
Manganese (Mn) , +7, +6, +4, +3
Iron (Fe) , +2, +5 , (+4), (+6)
Cobalt (Co) , +3 , +4
Copper (Cu) , +1
Zinc (Zn)
Vanadium (V) , +2, +3, +4
Molybdenum (Mo) , +2, +3, +4, +5
Nickel (Ni) , +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”
11/23/2018
L. Šoltés

21. Involvement of transition metals Fe Cu
11/23/2018
Involvement of transition metals Fe Cu
[Fe(II)---complex] + O2 → [Fe(III)---complex] + O2.-
2O H+ → H2O2 + O dismutation reaction
H2O2 + [Fe(II)---complex] → .OH + [Fe(III)---complex] + HO-
Cu(I)---complex
AscH- + 2[Fe(III)---complex] → H+ + 2[Fe(II)---complex] + DHA
Dismutation reactions are usually very slow
H2O2 + Cu(I)---complex → .OH + Cu(II)
+ [Fe(III)---complex] → H+ + [Fe(II)---complex] +
t1/2 = 10-9 s; site specific .OH generation !!!
+ [Fe(III)---complex] → [Fe(II)---complex] + DHA
Weissberger A. et al., Oxidation processes. XVI. The autoxidation of ascorbic acid. J Amer Chem Soc 1943, 65, 1934–1939
11/23/2018
L. Šoltés

22. Ergothioneine = (+)-charged thiol
Cu(I)---complex
H2O2 + Cu(I)---complex → .OH + Cu(II)
t1/2 = 10-9; site specific .OH generation !!!
11/23/2018
L. Šoltés

23. Reduction of cupric to cuprous ion by thiol
Motohashi N. et al., Complexing of cooper ion by ergothionenine. Chem Pharm Bull 1976, 24, 2364–2368
reduktívna chelatácia
Cu(II) + ES- → Cu(I) + ½ ESSE
Cu(I) + ES- → ES---Cu(I)
__________________________________________
1 Cu(II) + 2 ES- → ES---Cu(I) + ½ ESSE
11/23/2018
P. Rapta, K. Valachová, I. Valent, L. Šoltés

24. … Glycocalyx functions … cancer
Thiol application
Cu(II)
11/23/2018
11/23/2018
L. Šoltés 24

25. … Glycocalyx functions … cancer
H2O2 action
Cu(I)
11/23/2018
11/23/2018
L. Šoltés 25

26. … Glycocalyx functions … cancer
.OH
11/23/2018
11/23/2018
L. Šoltés 26

27. Hyaluronan (HA) fragmentation
11/23/2018
Hyaluronan (HA) fragmentation
.OH +
Initiation: HA + •OH → A• + H2O
11/23/2018
L. Šoltés

28. Hyaluronan fragmentation
11/23/2018
Hyaluronan fragmentation
HA fragments → immuno-stimulatory
11/23/2018
L. Šoltés

29. of lower-molar-masses stimulates immunity responses
… Glycocalyx functions … cancer treatment
of lower-molar-masses
stimulates immunity responses
Immunogenic
carbohydrates
immunogenic
11/23/2018
11/23/2018
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)
11/23/2018
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)
11/23/2018
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)
11/23/2018
K. Valachová

33. … Conclusions …
.OH
... „treatment“ ... Is it based on targeting DNA by .OH ?
Cancer Cell 31 (2017) 487–500
11/23/2018
L. Šoltés

34. … Conclusions …
.OH
... „treatment“ ... Is it a demasking the cells by .OH ?
Our TEAM: Hypotesis, speculation
11/23/2018
L. Šoltés et al.

35. … Conclusions …
.OH
... „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
11/23/2018
L. Šoltés et al.

36. … Conclusions …
11/23/2018
L. Šoltés

37. … Conclusions …
11/23/2018
K. Valachová et al.

38. Nature 551, 37–38 2 November 2017
The surprising history of an antioxidant
11/23/2018
L. Šoltés

39. Acknowledgements 11/23/2018 11/23/2018 The TEAM 39 MA Jardine
LP Khonde
11/23/2018
11/23/2018
The TEAM 39