High-Dose Vitamin C for Cancer Therapy: Comparison
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The idea that Vitamin C (Vit-C) could be utilized as a form of anti-cancer therapy has generated many contradictory arguments. Insights into the physiological characteristics of Vit-C, its pharmacokinetics, and results from preclinical reports, however, suggest that high-dose Vit-C could be effectively utilized in the management of various tumor types. Studies have shown that the pharmacological action of Vit-C can attack various processes that cancerous cells use for their growth and development. 

  • high-dose
  • anti-cancer
  • vitamin-C
  • pharmacological
  • pharmacokinetics
  • cancer
  • immunotherapy
  • ROS-scavenging systems

1. Introduction

Vit-C (C6H8O6)-ascorbate or/and ascorbic acid (Asc) is a vital water-soluble nutrient that humans and other primates cannot synthesize, owing to mutations in the gene that produces L-gulono-γ-lactone oxidase (GLO), the essential enzyme catalyzing the final step of Vit-C formation. Therefore, humans must receive their Vit-C from dietary sources [1,2][1][2]. Mice, however, unlike primates, are able to produce their own Vit-C [3,4][3][4].
Vit-C has several pivotal physiological functions in the body, through acting as an electron donor. In addition to being a powerful antioxidant, it also helps to maintain vital tissue structures and functions, by protecting key macromolecules such as proteins, fats, and DNA from oxidation [4]. Vit-C also functions as an enzyme co-factor (co-activator) for a variety of the biosynthetic enzymes that are involved in the production of hormones and the production of metabolic energy [5], along with another category of regulatory enzymes for certain genes [6,7][6][7]. In a recent study, it has been shown that Vit-C plays a pivotal role in controlling gene transcription via its action on transcription factors and epigenetic modifying enzymes [8,9][8][9]. Moreover, the nutritional deficiency of Vit-C is frequently related to anemia, bleeding gums, infections, scurvy, capillary haemorrhage, delayed wound healing, atherosclerotic plaques, muscle degeneration, and neurotic disorders [7]. Vit-C is often supplemented in high amounts to make up for such deficiencies, although toxicity is uncommon when taken in high dosages, unlike for fat-soluble vitamins. Vit-C is used in the prevention and treatment of a broad spectrum of conditions, including 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.

2. Historical Background and Justification of High-Dose Vitamin-C in Cancer Management

The notion that Vit-C may play a significant part in cancer prevention was originally postulated in the 1970s by Cameron and colleagues, who suggested that [17,18,19][17][18][19] high-dose Vit-C may increase the survival of cancer patients in their terminal stages. In the same decade, Pauling and Cameron conducted the first recorded research in which Vit-C was given to cancer patients. They demonstrated that giving 100 terminally sick cancer patients with 10 g of Vit-C daily led to excellent results, when compared to a thousand cancer patients who received the conventional treatment. It was shown that 10% of cancer patients who received Vit-C lived; while no malignancy cases that received the conventional treatment without Vit-C went on to survive [18]. The follow-up investigations supported these data. Murata and Morishige demonstrated, in research performed on Japanese patients with uterine malignancies and who received 5 to 30 g of Vit-C daily, that these individuals lived six times longer than those who received only 4 g of Vit-C daily. When a comparison was conducted between individuals who received Vit-C supplements and those who did not, it was shown that those who received Vit-C supplements had a 15% greater survival rate [20]. However, Moertel et al. found that high-dose Vit-C at 10 g per day had no advantage, when compared to placebo in two different investigations on 100 and 150 patients with late stage colorectal cancer (CRC) and patients with late stage cancers, respectively [21,22][21][22]. Now, new findings support the notion that high-dose consumption of Vit-C is associated with a decreased risk of the oral cavity, stomach, esophagus, pancreas, cervix, breast, and rectum cancers [23[23][24],24], and cancers with non-hormonal origins [25]. Furthermore, in terms of the amenable factors of risk for cancer, food counts as one of the most significant. Several independent study panels and committees have come to the conclusion that a high consumption of fruits and vegetables lowers the risk of developing various forms of cancer [26,27][26][27]; and in particular, it was shown that Vit-C intake was inversely linked to fatality rate [28]. In contrast, the consumption of vitamins A, C, and E, according to a research including 34,000 postmenopausal women, did not seem to be associated with a decreased risk for developing breast cancer [27]. In addition, according to some studies, intravenous Vit-C injection has been shown to be beneficial in the therapy of advanced malignancies [29,30][29][30]. Numerous mechanisms have been suggested to support the role of Vit-C in cancer treatment and prevention, including that of increasing the immune system activity; stimulating collagen synthesis; preventing metastasis, by inhibiting certain enzymatic reaction; inhibiting tumor-causing viruses; correcting for the lack of Vit-C, which is normally linked with cancer patients; wound healing in patients with cancer subsequent to surgery; improving chemotherapy sensitivity; decreasing chemotherapy toxicity; and neutralizing certain carcinogens [31]. Various recent experimental investigations have shown that when tumor cells are exposed to high doses of Vit-C, they suffer growth arrest [32,33][32][33]. Recent reports have also shown that Vit-C administration inhibits metastasis, tumor development, and inflammatory-associated cytokine production, while improving tumor inclusion and enhancing chemotherapy [34,35][34][35]. According to some reports, intravenous injection raises Vit-C levels over 70-fold when compared to oral delivery, and the efficacy of the therapy is inversely proportional to the excess amount of Vit-C [29,36][29][36]. For this reason, the ideal method of administration, the dosage, and the length of the treatment are being intensely debated. Recently reported pharmacokinetic data have improved ourthe knowledge about Vit-C transport regulation and given more clues about the therapeutic effectiveness of Vit-C. This has increased the interest in reconsidering the possibility of utilizing Vit-C in the inhibition of cancer development. Despite the fact that the procedures in these reports vary, the majority of the current research on Vit-C and cancer explores the impact of high-dose Vit-C on the formation and development of cancers, as well as the mechanisms of action that govern the anti-tumor impact of Vit-C [37]. In addition, studies have refocused on the consequences and usefulness of high intravenous Vit-C doses in cancer treatment. In vitro, pharmacological doses of Vit-C from 0.3–20 mmol/L preferentially target and kill cancer cells, compared to the usual physiological levels of Vit-C, which are 0.1 mmol/L. This tumor-killing phenomenon is due to the pro-oxidant characteristics of Vit-C, which, at high concentrations, facilitates the formation of hydrogen peroxide (H2O2), which may be an agent responsible for the anti-tumor impact of Vit-C and its use as a pro-drug in cancer therapies [38,39][38][39]. However, determining the exact contribution of Vit-C to clinical results is challenging, because patients are usually receiving several therapeutic regimens at the same time [40]. As a consequence, although the therapeutic benefit of high-dose Vit-C in cancer remission or development has not been unambiguously established, intravenous (i.v.) administration of the vitamin in high doses can enhance quality of life, even in the advanced stages of the disease [40].

3. Different Oxidized Forms of Vitamin-C

Given that Vit-C can occur in several oxidative states, interestingly, ascorbic acid is oxidized by ROS or/and free radicals, resulting in the formation of a reactive anion intermediate radical (Asc•−), which is subsequently oxidized to de-hydroascorbic (DHA) acid [41,42][41][42]. DHA, which has a relatively short half-life of just a few minutes [43], is converted to around 1–5% of the Vit-C inside the human cells [44], and it can be transferred into the cell or hydrolyzed irreversibly into 2,3-Diketo-L-gulonic (2,3-DKG) acid (C6H8O7). When 2,3-DKG is broken down into Ethanedioic acid (C2H2O4) and (2R,3S)-2,3,4-Trihydroxybutanoic acid (C4H8O5), the Vit-C level is significantly decreased [45]. DHA is quickly converted to Vit-C within the cell, by interacting with reduced glutathione (GSH) [45,46,47][45][46][47]. NADPH then recycles the oxidized glutathione (glutathione disulfide (GSSG)) and converts it back into GSH [45].

4. Enzymatic Activities of Vitamin-C

The biochemical activities of Vit-C may be ascribed to its chemical characteristics, which can donate electrons to a variety of molecules. Physiological ascorbate, which acts as an anti-oxidant at micromolar concentrations, may reduce ROS toxicity [42,48][42][48]. It may also act as a pro-oxidant at low plasma levels, which might be created via the i.v delivery of Vit-C [49]. Surprisingly, Vit-C also serves as a critical co-factor for many enzymes, easily giving electrons to prosthetic metal ions to attain a complete enzymatic action [44]. Overall, these proteins are divided into two categories: mono-oxygenases-containing copper and a-KG-, oxygen-, and iron-dependent dioxygenasesoxygen-, and iron-dependent dioxygenasesoxygen; and iron-dependent dioxygenases (α-KG; identified as 2-oxoglutarate (2OG))-dependent dioxygenases (α-KGDDs). α-KGDDs are iron-containing proteins that use oxygen (O2) as well as α-KG as an enzyme co-factor to produce succinate and CO2. α-KGDDs also catalyze various chemical processes involved in the construction of collagen, hypoxia-inducible factor 1-alpha (HIF1-α) stability, carnitine synthesis, tyrosine catabolism, and protein, DNA, and RNA de-methylation [50,51,52][50][51][52]. Accordingly, Vit-C is crucial for regulating a wide range of essential cellular activities.

5. ROS

As the therapeutic impact of high-dose Vit-C is strongly dependent on the formation of ROS, it is essential to define this term. The term “ROS” refers to a group of highly reactive chemical species formed when electrons escape from the mitochondrial electron transport chain (ETC; coenzyme Q) and interact with molecular O2, which is converted enzymatically to superoxide (O2•−) and dismutated to produce H2O2, which is then partially reduced to form hydroxide ions (OH−), hydroxyl radicals (HO•), and water (H2O) [53,54][53][54]. It is worth noting that the superoxide and the hydroxyl radical are together referred to as ROS free radicals [54]. Furthermore, a broad spectrum of substances may produce ROS exogenously. These include heavy metals, radiation, cigarette smoke, drugs, and xenosensors [55,56[55][56][57][58][59],57,58,59], among others. ROS play a key regulatory function in various metabolic pathways in living systems; hence, they are being continuously generated and eliminated. Under normal physiological circumstances, cells control ROS levels through their scavenging machinery [60]. However, under oxidative pressure, increased levels of ROS can result in DNA, protein, and lipid damage, which can potentially lead to cancer formation [61]. However, the action of ROS is essential for eradicating cancers at the molecular level. For these reasons, strategies to increase or eliminate ROS have been established. Tumors with higher ROS levels, for example, depend largely on their anti-oxidative stress defense systems. Drugs that elevate ROS can increase intercellular ROS amounts directly through ROS production (e.g., gadolinium, motexafin, elesclomol) or through inhibition of superoxide dusmutases (SODs) (e.g., ATN-224, 2-methoxyestradiol), and GSH (β-phenylethyl isothiocyanate (PEITC), buthionine sulfoximine (BSO)), which can produce massive ROS amounts, leading to cancer cell death [62,63][62][63]. However, under the low basal stress, normal cells appear to respond in a positive manner to enhanced ROS levels [63]. As a result, increasing ROS levels in all cells may be employed to selectively destroy cancer cells, a strategy discussed here in the context of high-dose Vit-C therapies.

6. Anti-Cancer Mechanisms of Vitamin-C

In recent years, numerous experimental reports have confirmed that low, millimolar range doses of pharmacological Vit-C may destroy tumors in vitro and prevent cancer development in vivo. The precise process by which certain tumor cells become susceptible to Vit-C, whereas wild type cells are unaffected is unclear. In fact, there is a wide range of mechanisms through which Vit-C may impact the progression of cancer. Conversely, the efficacy of this interaction is affected by a range of variables, such as the type of malignancy being managed and the different pathways that tumor cells utilize. In this section, wresearchers will look at how the anticancer mechanism of pharmacological ascorbate affects cancer cells. First, cancer cells, owing to their defective mitochondria and increased metabolic reliance, are more sensitive to oxidative stress than normal body cells [64]. Oxidative stress may aid in tumor growth via ROS, by enhancing the cell development and increasing the genetic imbalance. However, an excess of ROS may destroy cancer, and to avoid this deleterious effect, cancer cells utilize a variety of mechanisms that may block the negative effects of ROS [42,65][42][65]. Since cancer cells can utilize ROS for their development and growth [66], anti-oxidant treatments have been investigated as potential anti-cancer strategies, based on the notion that ROS promotes tumor development. Various studies, on the other hand, have shown no convincing indication of the effectiveness of antioxidant therapy in inhibiting tumor growth [67]. On the contrary, the antioxidant treatments seemed to facilitate cancer development and cancer cells metastasis in animal models [68,69][68][69] and increase the possibility for the development of certain cancers in humans [70,71][70][71]. These outcomes indicate that various malignancies depend on anti-oxidants for survival and, as a result, pro-oxidant drugs may be amenable in this case. Undoubtedly, pro-oxidant anti-tumor treatments, such as radiation, have been used for the treatment of patients with cancer [72]. On the other hand, the existing anti-oxidant therapies often cause substantial collateral damage, making it difficult to use them regularly [72]. Therefore, high-dose Vit-C may avoid these issues by targeting multiple tumor hallmarks, while simultaneously demonstrating no toxicity.

7. High-Dose Vitamin-C Enhances Cancer Immunotherapy

Numerous tumors resist the immune response by expressing high amounts of checkpoint proteins, such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) [195][73]. Therefore, anti-checkpoint (ICP) medicines targeting PD-1 or programmed cell death ligand 1 (PD-L1) and CTLA-4 have been licensed for the treatment of a variety of cancers. When used as monotherapy regimens, these medicines significantly increase survival rates and are relatively safe [196][74]. However, treatment failure occurs in more than half of individuals treated with these medicines as monotherapies. CTLA-4 and PD-1 combined inhibition has now been suggested to improve patient response rates and survival rates [196][74]. However, 50% of patients were subject to a higher toxicity as a result of the therapy regimen [197][75]. To reduce the toxicity and maximize the efficacy of these combinations, they must be used with drugs that are efficient in activating immune cells, namely cytotoxic T cells (CTLs), natural killer cells (NK cells), and antigen-presenting cells (APCs). In this regard, high-dose Vit-C has been proven to enhance cancer immunotherapies in several in vivo and in vitro studies. Accordingly, a combination of high-dose Vit-C (4 g/kg) with anti-CTLA-4 (200 μg) and anti-PD-1 (250 μg) antibodies resulted in significant tumor impairment and remission via the infiltration and activation of anti-cancer adaptive immunity (CD8 T and CD4 T cells), especially CD8 T cells. This activation was revealed by the production of higher interferon-gamma (IFN-γ) and the increased effectiveness of immune checkpoint inhibitors in various animals and in vitro models [35]. Along the same line, after addition of high-dose Vit-C (1.5 M) with anti-PD1 (200 μg) antibodies in a lymphoma mouse model, high-dose Vit-C therapy improved tumor immune recognition, and resulted in enhanced macrophage and cytotoxic T cell infiltration, which is not seen with anti-PD1 treatment alone. In addition, anti-PD1 antibodies inhibited the PD-1/PD-L1 axis’s inhibitory effect on APCs, CD8+ T, and NK cells. However, anti-PD1 alone is more effective in directly activating these cells than high-dose Vit-C. Indeed, the combined therapy significantly increased the production of IL-12 by APCs and granzyme B by cytotoxic cells (CD8+ T cells and NK cells) as compared to either of the drugs alone [198][76]. An additional study in the RCC mice model demonstrated that high-dose Vit-C therapy alone led to tumor infiltration by both CD4+ and CD8+ T cells and elevated the ratio CD8+/CD4+, while regulating the production of numerous cytokines and chemokines. Anti-PD-L1 antibody injection alone increased intratumoral CD4+ and CD8+ T cells significantly. However, the infiltration of CD4+ and CD8+ T cells, as well as the CD8+/CD4+ ratio, increased considerably when high doses of Vit-C were coupled with anti-PD-L1 antibodies. Specifically, Vit-C stimulates TET2, which in turn activates IRF1, which eventually binds to STAT1, to enhance the expression of PD-L, making tumor cells more susceptible to immunotherapy [199][77]. These findings indicate that high-dose Vit-C and the anti-PD-L1 antibody can act synergistically to eliminate tumor cells, and that the immunotherapy effect of Vit-C-anti-PD-L1 combination is TET2-dependent. Supporting this notion, in mouse melanoma and colon tumors, high-dose Vit-C dramatically enhanced T helper 1 (Th1) chemokines and tumor-infiltrating lymphocytes in the IFN-γ/JAK/STAT/TET axis, resulting in improved anti-tumor immunity and anti-PD-L1 effectiveness. Specifically, Vit-C enhanced IFN-γ-stimulated production of three Th1-type chemokines and PD-L1 genes in a TET2-dependent sense, where the activated TET2 binds to and increases the levels of 5hmC in the CXCL10 and PD-L1 promoters. However, loss of TET2 significantly decreased the ability of Vit-C to activate tumor-infiltrating CD8+ and CD3+ cells, indicating that TET2 is the primary target for Vit-C in enhancing the effectiveness of the anti-PD-L1 therapy [200][78]. TET activity may be used as a biomarker to predict the efficacy and response of patients to an anti-PD-1/PD-L1 therapy, and high-dose Vit-C could be regarded as an adjuvant to immunotherapy through the achieved stimulation of the TET activity, especially for solid tumors expressing significantly lower levels of 5hmC. Based on the ability of high-dose Vit-C to produce massive amounts of ROS in tumor cells, a recent study reported that Vit-C and oncolytic adenoviruse (oAds) combination therapy increased the production of ROS significantly, as compared to Vit-C or oAds monotherapies. This increased production of ROS, in turn, induced immunogenic cell death (ICD), which was confirmed by the increase in the calreticulin (CRT) translocation onto the cell membrane and by the upregulation of two ICD markers, heat shock protein 90 (HSP90) and high mobility group box 1 (HMGB1), which successfully stimulated dendritic cell (DC) maturation [201][79]. The results of the combined treatment were further evaluated in a variety of tumor-bearing mice. As a result of DC (CD11c+MHC-II+, CD80+, and CD86+) maturation and activation, the Vit-C and oAds recipe also expanded the numbers of CD3+, CD4+, and CD8+ T cells, particularly CD8+ T cells (IFN-γ, STAT1, CD137, IL-12p35, Granzyme B, and Perforin), in the tumor tissues and caused the upregulation of genes associated with T-cell motility, for example CCL3, CCL4, CCL5, and CXCL10 [201][79]. In addition, the combination therapy also significantly reduced the proportion of Regulatory T cells (Tregs-FoxP3+CD25+) and increased the ratios of CD4+ T cells to Tregs and CD8+ T cells to Tregs. At the same time, neither Vit-C or oAds single-therapy nor Vit-C and oAds combination therapy diminished the ratio of MDSCs (Gr-1+CD11b+) in cancer tissues. However, single-therapy with Vit-C alone or oAds alone reduced the ratio of Tumor-associated macrophages (TAMs-F4/80+CD11b+) in tumor tissues. While the combined Vit-C and oAds reduced the proportion of TAMs (M2 polarized TAMs (CD206+ F4/80+CD11b+) in tumor tissues. All these events, together, mediated the tumor suppression in tumor-bearing mice and in cell culture treated with Vit-C and oAds combined therapy [201][79] (Figure 1).
Figure 1. Systematic effect of high-dose Vit-C on cancer immunotherapy. (1) Cancer cells resist and inhibit the immune response to prevent successful cancer eradication. (2) High-dose Vit-C combined with ICP therapy. (3) High-dose Vit-C activates APCs to increase cytokines (IL-12 and IFN-γ), and also enhances the phagocytic activity of the APCs; in addition, high-dose Vit-C can also activate and increase the intratumoral infiltration of both CTLs and NK cells. (4) As a result, these cells in turn produce more cytokines, chemokine, and cytotoxic mediators (perforin and garnzyme). (5) The ICP therapies bind to their target proteins on cancer cells and make them susceptible to potential cellular lysis mediated by CTLs and NK. ICP, immune check point; Vit-C, vitamin-C; APCs, antigen presenting cells; IFN-γ, interferon gamma; IL-12, interleukin 12; NK cells, natural killer cells; CTLs, cytotoxic T lymphocytes.
Altogether, these findings imply that high-dose Vit-C and ICP therapies have synergistic anti-tumor effects. It should be noted that, to the best of outhe researchers' knowledge, only a few studies have reported the utilization of high-dose Vit-C and immunotherapies to date. Indeed, given the huge promise of immunotherapy in anti-cancer treatment, these results are very encouraging, and they indicate a possible combination approach for transforming the tumor microenvironment and increasing the therapeutic breadth of immunotherapy. However, no clinical trials have been conducted on the use of Vit-C in conjunction with ICB treatments, and additional investigations are required to give more emphasis on this important interaction; paving the way towards effective clinical trials.

8. Antioxidant Systems That Might Inhibit the Effect of High-Dose Vitamin-C Therapy

Cells use a range of mechanisms to counteract ROS-induced oxidative stress, all of which are mediated by different antioxidant regulatory systems, including CAT, superoxide dismutases (SODs), glutathione peroxidases (GPXs), and Peroxiredoxins (PRDXs) [63,202,203][63][80][81]. Furthermore, these systems convert O2•−, OH•, and H2O2 into H2O and O2 molecules. Additional systems that control ROS include co-factors for the PRDX and GPX-catalyzed processes of reduced GSH and reduced thioredoxin (TRX), respectively; while, GSH is also employed by glutathione-S-transferases (GSTs) to inhibit ROS production (Figure 2), (Table 1) [204][82]. Additionally, cells can regulate the ROS generated by Fenton reaction indirectly through the FTH, which mediates the suppression via LIP sequestration (Figure 2) [205][83], which in turn reduces ROS production. Surprisingly, cancer cells may be able to adapt to the toxicity caused by ROS after receiving a high-dose of ascorbate, by upregulating the intracellular antioxidant proteins and non-enzymatic molecules.
Figure 2. Inhibition of ROS generated by high-dose Vit-C via different antioxidant systems. Cancer cells may express different antioxidant systems that may together scavenge ROS. Through recycling of Fe(II)/Fe(III) and the Fenton reaction, high-dose Vit-C produces massive ROS concentrations that, in turn, damage cancer cells. In this regard, SOD converts O2•− to H2O2, then CAT, PRDXs, GSH, TRXs, GSTs, and GPxs, together, convert the produced H2O2 to H2O and cellular O2, and this may prevent the production of OH•. In addition, FTH prevents the formation of ROS through massive sequestration of the LIP. Moreover, this collectively inhibits ROS generation. Vit-C, vitamin-C; SODs, superoxide dismutases; CAT, catalase; PRDXs, Peroxiredoxins; GSTs, glutathione-S-transferases; TRXs, Thioredoxins; GPxs, glutathione peroxidases; GSH, reduced glutathione; GSSG, glutathione disulfide; FTH, ferritin heavy chain; LIP, labile iron pool.
SODs are potent metalloenzymes found in all living organisms that catalyze the transition of O2•− into O2 and H2O2 by alternating oxidation-reduction of metal ions existing in the active site of SODs; thus, preventing the harmful effects of ROS. Based on the metal co-factors located in the active sites, SODs are classified as Manganese-SOD (Mn-SOD), Iron-SOD (Fe-SOD), Nickel-SOD, and Copper-Zinc-SOD (Cu, Zn-SOD) [206,207][84][85]. In cancer, for instance, Mn-SOD was found to play the role of a double edged sword agent, as this protein was differentially expressed in different tumors [207,208][85][86]. In breast cancer, Mn-SOD gene expression is drastically altered between early and advanced stage, in such a way that it is decreased in the early breast cancer stage and increased in the advanced stage. Furthermore, via suppressing O2•− and H2O2, this protein was linked to the invasive and angiogenic characteristics of breast tumor cells [209][87]. However, Mn-SOD in cancer development is still controversial, as it can be considered as a protective antioxidant, as well as a pro-oxidant during cancer progression. CAT is an important enzyme of the peroxisomes that metabolizes H2O2 to form H2O and O2, as a form of defense against oxidative stress [210][88]. CAT is absent in the mitochondria; therefore, GPx mediates the reduction of H2O2 to H2O, and of lipid peroxides to their corresponding alcohols [202][80]. In cancer, CAT serves to protect malignant cells from intercellular ROS damage, given that the ability to withstand ROS action is essential for tumor development [211][89]. Expression of CAT has also been shown to vary between cancerous and non-cancerous tissues. The protein is expressed differentially in various malignancies as well [212][90]. Glutathione peroxidases (GPxs) are a group of proteins that use GSH as a co-substrate to reduce H2O2 to H2O, and lipid peroxides to their corresponding alcohols [202,213,214][80][91][92]. Notably, because they need selenium as a co-factor for their action, GPxs are classified as seleno-cysteine peroxidase [213][91]. In cancer, these proteins can serve as both protective antioxidants, as well as pro-oxidants. For example, in CRC, GPxs was found to reduce cancer growth by acting as a tumor suppressing gene [215][93], while in breast cancer, high expression of GPx was found to develop resistance to chemotherapy, leading to a poor response to treatment in breast cancer patients [216][94]. Peroxiredoxins (PRDXs) are a widespread group of thiol-dependent peroxidases that catalyze the conversion of H2O2, alkyl hydroperoxides, and peroxynitrite, and alkyl hydroperoxides, and peroxynitrite to H2O, and the corresponding alcohol and nitrite [217][95]. Moreover, PRDXs have been shown to have a low or high expression in cancer in several investigations. Several in vitro and in vivo investigations have found that high levels of PRDX expression may either prevent or stimulate tumor development [217][95], depending on the type of cancer, the stage of the disease, and the PRDX family member [217,218,219][95][96][97]. Thioredoxins (TRXs) are a broad family of small dithiol proteins that share the thioredoxin fold motif [220,221][98][99] responsible for reducing the oxidized cysteine residues on cellular proteins [222][100]. As part of its disulfide reductase activity and manipulation of the protein dithiol/disulfide balance, NADPH, thioredoxin, and TrxR are all components of the thioredoxin system, which is a key defense mechanism against ROS [223][101]. In cancer, Thioredoxin-1 (Trx-1), for example, is expressed in great quantities in several malignancies and has been linked to worse patient survival rates, in addition to resistance to chemotherapy [224][102]. Furthermore, the protein enhances VEGF expression in vitro and angiogenesis in vivo, through regulating and increasing transcription factors such as HIF1-α [225][103]. Reduced glutathione (GSH) is the most prevalent low-molecular-weight non-enzymatic thiol linear tri-peptide comprising L-glutamine, L-cysteine, and glycine molecules in living organisms, and it plays an important role in redox homeostasis, which protects against the oxidative stress caused by ROS [226][104]. Importantly, through enzymatic reactions, GSH directly and indirectly scavenges free radicals and other ROS, as well as reactive nitrogen species (RNS) [227][105]. Since it includes N-L-gamma-glutamyl-cysteinyl glycine or L-glutathione, the protein has a sulfhydryl (SH) group on the cysteinyl side, which contributes to the strong electron-donating properties of the protein. Under normal physiological conditions, GSH is present in its reduced form, and its oxidation to create oxidized GSSG is mediated by interactions with free radicals and/or antioxidant enzymes, such as GSH peroxidases, which use GSH as a cofactor to reduce H2O2 and phospholipid hydroperoxide [228][106]. However, glutathione reductase reduces GSSG via a NADPH-dependent mechanism, to keep the intracellular concentration of GSSG at extremely low concentrations [229][107]. In cancer cells, GSH may act as a protective factor against the ROS produced by high-dose Vit-C. For instance, it has been suggested that increased GSH levels and the rate of GSH production in malignant cells are responsible for the resistance to chemotherapy and radiation therapy [228,230][106][108]. In addition, research conducted on DU-145, a human prostate cancer cell line, showed that higher GSH levels were associated with drug resistance. Similar results were also reported in ovarian cancer [228][106]. Glutathione-S-transferases (GSTs) are a superfamily of abundant enzymes (α, μ, ω, π, θ, and ζ) that protect cellular components from the oxidative stress caused by ROS [231][109]. GSTs promote the conjugation of GSH to various endogenous and exogenous electrophiles, and this represents the first step in the elimination of toxic compounds by the mercapturic acid pathway [232][110], resulting in the formation of less reactive and more soluble molecules. There is a growing body of evidence that suggests that GST overexpression plays a vital role in cancer resistance and progression. Drug resistance may be triggered by GSTs in two ways: either directly via detoxification, or by inhibiting the MAP kinase pathway [232][110]. Furthermore, GST knockdown inhibited cancer development, suggesting that an increase in ROS levels may be related to impaired cell proliferation and growth [233][111]. FTH, ferritin is the main iron storing protein in the cell and is composed of 24 peptide chains divided into two subunits: FTH, and ferritin light chain (FTL) [81][112]. These proteins come together to create an iron-sequestering complex. Through its ferroxidase activity, FTH converts excess cellular iron into the harmless ferric ion, which is then stored in a ferritin complex; thereby, preserving proper iron homeostasis [81][112]. Moreover, FTH functions as a regulator that sequesters the LIP into low level concentrations. FTH was shown to be an important facilitator of the antioxidant and protective properties of NF-κB. FTH is induced downstream of NF-κB and is necessary to avoid persistent JNK activation and, hence, the apoptosis produced by TNF-α. The suppression of JNK signaling by FTH is dependent on the prevention of ROS production via sequestration of LIP [205][83]. FTH overexpression in cancer cells may lead to resistance to high-dose Vit-C therapy, which may induce massive ROS release. Kiessling et al. reported that in this scenario, since FTH is activated downstream of NF-κB, downregulation of this transcription factor in cutaneous T-cell lymphoma results in reduced expression of FTH, which leads to an increase in LIP, causing huge formation of ROS [174][113]. Conversely, siRNA-mediated direct downregulation of FTH resulted in ROS-dependent apoptosis. However, T cells from healthy subjects do not demonstrate FTH downregulation and, hence, do not show an increase in iron or cell death when NF-κB is inhibited. Furthermore, in breast cancer cell lines, FTH overexpression was related to modifications in the subcellular location of these molecules, as shown by an increased level of nuclear ferritin and a reduced level of the LIP [234][114], which affected ROS production. Overexpression of ROS-scavenging systems in TME might be associated with cancer development and progression, and these systems could have a direct impact on the toxicity caused by high-dose Vit-C therapy, which is heavily reliant on free radicals. Furthermore, overexpression of FTH, which facilitates the sequestration of the LIP, may indirectly impact the generation of ROS caused by high-dose Vit-C. Moreover, cancer cells may overexpress many scavenging systems, which are occasionally expressed in a subservient manner. To improve the efficacy of this therapy, studies investigating the cancer-specific expression of these systems, in terms of applying high-dose Vit-C, are strongly encouraged. Studies to elucidate the molecular pathways that can be employed by these systems, to give a greater protection against the oxidative stress and that can be exploited by specific tumors, are also strongly suggested.
Table 1.
The function of defense systems and their sub-cellular localizations.

Defense System

Sub-Cellular Localization(s)

ROS Type and System Function

Ref.

SODs

Cytosol and Peroxisomes

O2•− to O2 and H2O2

[202][80]

CAT

Peroxisomes

H2O2 to H2O and O2

[202][80]

GPxs

Mitochondria and Cytosol

H2O2 to H2O

lipid peroxides to alcohols

[202][80]

PRDXs

Cytosol, Mitochondria, Nucleus And Endoplasmic reticulum

H2O2 to H2O

[217][95]

TRXs

Cytosol, Mitochondria, Nucleus

H2O2 to H2O and O2

[220,221][98][99]

GSH

Cytosol, Mitochondria, Nucleus And Endoplasmic reticulum

H2O2 to H2O

[227,229][105][107]

GSTs *

Cytosol, Membrane-bound

conjugates with reduced GSH)

[232][110]

FTH *

Nucleus, Lysosome, Cytoplasm

Sequester Fe(II) to inhibit ROS generation

[81][112]

SODs, superoxide dismutases; CAT, catalase; PRDXs, Peroxiredoxins; GSTs, glutathione-S-transferases; TRXs, Thioredoxins; GPxs, glutathione peroxidases; GSH, reduced glutathione; GSSG; FTH, ferritin heavy chain, indirect ROS formation inhibition *.

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