Elevated Ferritin in cancer is mostly due to the neoplastic process and rarely reflective of iron storage or nutriture [PMID: 23891969] – It can however be a marker of progression. That said, as the MOA of HDIVC uses Fe and Cu to flip electrons and cause the H2O2 burst and so iron availability is important in the MOA of HDIVC, and it appears that elevated ferritin may be helpful [PMID: 16799870, PMID: 9133640]. In our experience we have not seen any negative reactions or adverse events using HDIVC in cancer patients with elevated ferritin. In respect to ascorbate and iron absorption (this connection is often asked about as well) – that is a purely GI effect of ascorbate [PMID: 23481043] so (regardless of the general non-relationship of cancer ferritin elevations and iron status) HDIVC is not much of an issue in that regard oncology cases with elevated ferritin. So, as mentioned above, the use of HDIVC in oncology cases with elevated ferritin is not generally an issue except that it may make the HDIVC work better.
In a case of hemochromatosis, however, the risk of oxidation is to be considered. If the patient who has hemochromatosis requires an oxidative therapy (infection, cancer etc…) then it is fine. If that is not the indication then lower doses of IVC are appropriate.
Some additional papers that may help: The significance of ferritin in cancer: anti-oxidation, inflammation and tumorigenesis.
“The iron storage protein ferritin has been continuously studied for over 70 years and its function as the primary iron storage protein in cells is well established. Although the intracellular functions of ferritin are for the most part well-characterized, the significance of serum (extracellular) ferritin in human biology is poorly understood. Recently, several lines of evidence have demonstrated that ferritin is a multi-functional protein with possible roles in proliferation, angiogenesis, immunosuppression, and iron delivery. In the context of cancer, ferritin is detected at higher levels in the sera of many cancer patients, and the higher levels correlate with aggressive disease and poor clinical outcome. Furthermore, ferritin is highly expressed in tumor-associated macrophages which have been recently recognized as having critical roles in tumor progression and therapy resistance. These characteristics suggest ferritin could be an attractive target for cancer therapy because its down-regulation could disrupt the supportive tumor microenvironment, kill cancer cells, and increase sensitivity to chemotherapy. In this review, we provide an overview of the current knowledge on the function and regulation of ferritin. Moreover, we examine the literature on ferritin’s contributions to tumor progression and therapy resistance, in addition to its therapeutic potential.”
And Ascorbate-mediated iron release from ferritin in the presence of alloxan. ;
“Release of iron from ferritin requires reduction of ferric to ferrous iron. The iron can participate in the diabetogenic action of alloxan. We investigated the ability of ascorbate to catalyze the release of iron from ferritin in the presence of alloxan. Incubation of ferritin with ascorbate alone elicited iron release (33 nmol/10 min) and the generation of ascorbate free radical, suggesting a direct role for ascorbate in iron reduction. Iron release by ascorbate significantly increased in the presence of alloxan, but alloxan alone was unable to release measurable amounts of iron from ferritin. Superoxide dismutase significantly inhibited ascorbate-mediated iron release in the presence of alloxan, whereas catalase did not. The amount of alloxan radical (A.(-)) generated in reaction systems containing both ascorbate and alloxan decreased significantly upon addition of ferritin, suggesting that A.(-) is directly involved in iron reduction. Although release of iron from ferritin and generation of A.(-) were also observed in reactions containing GSH and alloxan, the amount of iron released in these reactions was not totally dependent on the amount of A.(-) present, suggesting that other reductants in addition to A.(-) (such as dialuric acid) may be involved in iron release mediated by GSH and alloxan. These results suggest that A.(-) is the main reductant involved in ascorbate-mediated iron release from ferritin in the presence of alloxan and that both dialuric acid and A.(-) contribute to GSH/alloxan-mediated iron release.”
Additionally: Iron bound to ferritin catalyzes ascorbate oxidation: effects of chelating agents.
“Ferritin is the main intracellular iron storage protein. Ferritin iron may be released by many reducing agents including ascorbate. In this work we report ferritin to catalyze the oxidation of ascorbate. The kinetics of this process were studied in detail in phosphate buffer (pH 7.40), at 37 degrees C by using the Clark electrode technique and ESR. The catalytic effect of ferritin manifested itself as the increase both in the rate of oxygen uptake and steady-state concentration of the ascorbate radical. The ferritin catalytic activity was found to be modified by iron chelators, EDTA. Desferal (DFO) as well as by ferrozine (FRZ) which is widely used in kinetic studies on ferritin iron release thanks to the formation of a coloured complex with Fe(II). While EDTA promotes the catalytic action of ferritin, DFO and FRZ diminished it. From the comparison of the kinetics of ascorbate oxidation obtained in the current work and data on the kinetics of ferritin iron release reported by Boyer and McCleary ((1987) Free Rad. Biol. Med. 3, 389-395), we conclude that iron bound to ferritin rather than the iron released is likely responsible for ferritin catalytic action. In addition, it has been concluded that the use of FRZ as an analytical reagent in kinetic studies of reductive ferritin iron release requires taking into account the competitive character of the formation of the Fe(II)-FRZ complex.”
Transferrin iron uptake is stimulated by ascorbate via an intracellular reductive mechanism. Although ascorbate has long been known to stimulate dietary iron (Fe) absorption and non-transferrin Fe uptake, the role of ascorbate in transferrin Fe uptake is unknown. Transferrin is a serum Fe transport protein supplying almost all cellular Fe under physiological conditions. We sought to examine ascorbate’s role in this process, particularly as cultured cells are typically ascorbate-deficient. At typical plasma concentrations, ascorbate significantly increased Fe uptake from transferrin by 1.5-2-fold in a range of cells. Moreover, ascorbate enhanced ferritin expression and increased Fe accumulation in ferritin. The lack of effect of cycloheximide or the cytosolic aconitase inhibitor, oxalomalate, on ascorbate-mediated Fe uptake from transferrin indicate increased ferritin synthesis or cytosolic aconitase activity was not responsible for ascorbate’s activity. Experiments with membrane-permeant and -impermeant ascorbate-oxidizing reagents indicate that while extracellular ascorbate is required for stimulation of Fe uptake from Fe-citrate, only intracellular ascorbate is needed for transferrin Fe uptake. Additionally, experiments with l-ascorbate analogs indicate ascorbate’s reducing ene-diol moiety is necessary for its stimulatory activity. Importantly, neither N-acetylcysteine nor buthionine sulfoximine, which increase or decrease intracellular glutathione, respectively, affected transferrin-dependent Fe uptake. Thus, ascorbate’s stimulatory effect is not due to a general increase in cellular reducing capacity. Ascorbate also did not affect expression of transferrin receptor 1 or (125)I-transferrin cellular flux. However, transferrin receptors, endocytosis, vacuolar-type ATPase activity and endosomal acidification were required for ascorbate’s stimulatory activity. Therefore, ascorbate is a novel modulator of the classical transferrin Fe uptake pathway, acting via an intracellular reductive mechanism.
