metabolic activity, oxygen transport, and DNA synthesis
Iron is found in the human body in the form of haemoglobin in red blood cells and growing erythroid cells.
macrophages contain considerable quantities of iron
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)
excess iron is retained in the liver cells
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)
labile iron pool (LIP)
LIP is toxic to the cells owing to the production of massive amounts of ROS.
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
Fe(II) catalyzes the formation of OH• and OH− during the interaction between H2O2 and O2•− (Haber–Weiss reaction)
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
Vit-C-stimulated iron absorption
reduce cellular iron efflux
high-dose Vit-C may elevate cellular LIP concentrations
ascorbate enhanced cancer cell LIP specifically by generating H2O2
Vit-C produces H2O2 extracellularly, which in turn inhibits tumor cells immediately
tumor cells have a need for readily available Fe(II) to survive and proliferate.
Tf has been recognized to sequester most labile Fe(II) in vivo
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
free irons, especially Fe(II), increase Vit-C autoxidation, leading to H2O2 production
iron metabolism is altered in malignancies
increase in the expression of various iron-intake pathways or the downregulation of iron exporter proteins and storage pathways
Fe(II) ion in breast cancer cells is almost double that in normal breast tissues
macrophages in the cancer microenvironment have been revealed to increase iron shedding
Advanced breast tumor patients had substantially greater Fe(II) levels in their blood than the control groups without the disease
increased the amount of LIP inside the cells through transferrin receptor (TfR)
Warburg effect, or metabolic reprogramming,
Warburg effect is aided by KRAS or BRAF mutations
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
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
Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
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
mega-dose Vit-C influences energy metabolism by producing tremendous amounts of H2O2
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.
facilitates the transport of intra and extra cellular liquids which helps the organism to eliminate the toxic products
The increased number of insulin receptors on the tumor cell, in comparison to the normal one, allows the before mentioned 2 factors to act predominantly
Increased permeability after the insulin effect on the cellular membrane results in increased intracellular quantity of antitumor agents
have other endocrine effects: directly stimulates suprarenal gland to produce epinephrine and glucocorticoid hormones and stimulates ACTH secretion. These endocrine effects also have a positive influence on the regenerating processes
Insulin influences the intracellular metabolism of the tumor cell, which leads to increase of the number of cells in phase S, where they are with highly sensitive to specific chemotherapeutics.
After the first 6 IPT applications overall (groups A and B) response to treatment on PSA criteria shows partial effect and stabilization in 12 of 16 (75%) patients
After the 10th IPTLD application or 3 months after starting treatment, complete response, partial response, and stabilization were observed in 4 of 9 (66.6%), while in 3 of 9 (33.3%) was registered complete effect
the advanced stage of disease in patients treated
Quality of life after the second IPTLD application is significantly improved