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Oncology
The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis.
- ascorbate
- cancer
- ferroptosis
- iron
- labile iron pool
1. Introduction
For 2020, the cancer incidence, estimated for 36 cancer types in 185 countries, was about 19.3 million with a total of nearly 10.0 million deaths [1,2]. Worldwide, 28.4 million new cancer cases are expected for the year 2040, a 47% increase from 2020 [2]. A detailed cancer diagnosis is essential for appropriate and effective treatment including cancer phenotype, tumor stage, and the personal circumstances of patients. Some of the most common cancer types have high cure probabilities when detected early and treated accordingly. Unfortunately, a significant variation in treatment availability exists between countries of different income levels. Comprehensive treatment is reportedly available in more than 90% of high-income countries but in less than 15% of low-income countries [3]. Remarkably, small cell lung cancer (SCLC), pancreatic ductal adenocarcinoma (PDAC), advanced ovarian cancer (AOC), triple-negative breast cancer (TNBC), and glioblastoma (GBM) are very aggressive solid tumors displaying highly invasive phenotypes and treatment resistance [4]. For these tumor entities, there is currently an urgent need for novel treatment approaches. Vitamin C (ascorbic acid, ascorbate) is not only an essential human micronutrient [5] with a recommended daily intake of 110 mg [6] but also a bioactive substance acting as a prodrug, e.g., for the formation of hydrogen peroxide (H2O2), especially in pharmacological concentrations, intravenously administrated in the range of grams per kilogram bodyweight. Intravenous ascorbate is widely used by complementary and alternate medicine practitioners, commonly to treat infectious diseases, cancer, and fatigue [7]. After excluding potential contraindications, such as glucose-6-phosphate dehydrogenase deficiency, impaired renal function, and kidney stones, intravenous high-dose vitamin C treatment is an option [8,9]. Sealed vitamin C solutions are stable at room temperature [10] and moreover, vitamin C is very cost-effective and globally available. These criteria make the exploration of parenteral high-dose vitamin C a promising approach for cancer therapy [10,11] which is currently being evaluated in clinical trials. In the early 1970s, it was successfully demonstrated that intravenous administration of high-dose ascorbate contributes to a significant prolongation of survival in end-stage cancer patients [12,13,14]. Interestingly, the peak plasma concentration found after ascorbate ingestion was 220 μM [15]. Liposomal formulations may result in slightly higher peak plasma ascorbate concentrations after oral application by increasing the plasma half-life and by enhancing bioavailability [16]. Nevertheless, antitumoral activity seems to be mainly obtained in the millimolar range which can only be achieved parenterally [17,18,19]. Accordingly, pharmacologic vitamin C as mono- or combination therapy is described as requiring i.v. administration of up to 1.5 g vitamin C per kilogram body weight, yielding plasma concentrations of ≥20 mM [20]. It is suggested that this infusion should be performed at least two times a week for a minimum of eight weeks, according to the evaluation of 71 preclinical and 57 partly ongoing early clinical trials [21]. However, confirmatory placebo-controlled double-blind studies on the efficacy and tolerability of ascorbate use in larger patient cohorts are currently still lacking for definitive proof and implementation of pharmacological ascorbate’s use in tumor therapy. Nevertheless, ascorbate therapy was shown not only to be well-tolerated but also to relieve pain and to improve quality of life in the context of palliative care [7,20,21,22]. Combined treatments, comprising standard treatment protocols (chemotherapy, radiotherapy, targeted therapy, and others) and high-dose vitamin C have mostly been shown to improve therapeutic efficacy, disease control, and objective response rates in some early clinical studies of small study cohorts [7,20,21,22]. The anti-cancer mechanisms by which vitamin C acts on malignant cells include immune modulatory effects, epigenome regulation, collagen synthesis, inhibition of epithelial-mesenchymal transition (EMT) and invasion, and pro-oxidant activity [21]. The most frequently described mechanism is a selective cytotoxic effect on cancer cells (pro-oxidative), which increases the redox imbalance and causes oxidative stress, DNA damage, and an arrest of anti-oxidative enzymes, underlining the various antitumoral effects of vitamin C in relation to the respective treatment [23,24,25,26,27,28,29,30].
2. Generation of Reactive Oxygen Species and Intracellular Toxicity
Vitamin C is a water-soluble ketolactone with two ionizable hydroxyl groups [31]. In the absence of catalytic metals, the spontaneous oxidation of ascorbate proved to be quite slow in various buffer solutions at pH 7.0 [32]. The dominant species for vitamin C at pH 7.0 are mainly ascorbate (AscH− (99.9%)), its protonated form AscH2 (0.1%), and the dianion Asc2− (0.005%) [31,33]. The predominant mechanism underlying the anticancer activity of parenteral pharmacological vitamin C is based on its ability to act as a prodrug [34,35] due to preferential steady-state formation of the ascorbate free radical (AFR; Asc•−) and H2O2 in the extracellular space but minimal formation in the blood, requiring a threshold Asc•− concentration of at least ≈ 100 nM [15,16,35]. In the blood, Asc•− formation is inhibited by red blood cell membrane-reducing proteins [36] and H2O2 is immediately degraded by plasma catalase and red blood cell glutathione peroxidase [34,37,38]. Asc•− formation exponentially correlates to an increasing ascorbate concentration in the extracellular fluid. The lost electron reduces a protein-centered iron atom and donates an electron to oxygen, forming superoxide (O2•−) with subsequent dismutation to H2O2 extracellularly [35,39]. Plasma membrane-associated nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) can also contribute to the formation of O2•− that dismutates to H2O2 [40], which can freely diffuse across the plasma membrane or enter the cytosol through peroxiporins.
Generally, members of the NOX family and a considerable number of mitochondrial respiratory chain oxidases are the main generators of H2O2 [41,42,43,44,45,46]. Additionally, other cellular organelles also contribute to H2O2 production, e.g., the endoplasmic reticulum and peroxisomes [47,48,49,50]. At low intracellular concentrations, H2O2 acts as a signaling agent that, e.g., promotes proliferation and survival [45,51,52]. However, H2O2 concentrations produced by pharmacological ascorbate injection are higher than survival-promoting H2O2 concentrations, leading to cell death instead [35]. Among the various oxygen metabolites, H2O2 is considered to be the most suitable for redox signal transduction and also modulates the activity of transcription factors [53]. Further, mitochondrial H2O2 metabolism may also affect calcium signaling [54].
Originally, ascorbate was thought to have prodrug activity, as also suggested by Chen et al. [35], due to selective H2O2 formation in the extracellular space, but not in the blood, triggered by external pharmacological ascorbate concentrations [34]. In addition, there is evidence that when cells are exposed to an external source of H2O2, the rapid degradation of H2O2 inside the cell provides the driving force for the formation of the gradient across the plasma and other subcellular membranes [55]. The steady-state concentration of H2O2 in intact cells was calculated to be about 1–10 nM [46]. Supraphysiological concentrations of H2O2 (>100 nM), e.g., induced by high-dose ascorbate, lead to intracellular accumulation of H2O2, destruction of biomolecules, disrupted redox signaling, cell growth arrest, and cell death [34,46]. Therefore, H2O2 uptake and distribution in cells and tissues are subject to gradient kinetics (gradients between extracellular and intercellular as well as between subcellular cellular compartments [46]).
The initiated formation of extracellular H2O2 promotes its accumulation in tumor tissue [56]. Accumulation of cellular H2O2 mediates increased toxicity in sensitive cells and displays oxidatively modified proteins in mitochondrial fractions correlating with a decline in the intracellular ATP level [57] via multiple pathways [35]. For example, H2O2 can cause DNA single-strand breaks that are usually repaired by polyADP-ribose polymerase (PARP), but increased PARP activity can consume intracellular nicotinamide adenine dinucleotide (NAD+), leading to ATP depletion [58,59]. In addition, cancer cells that rely on anaerobic metabolism for ATP generation (Warburg effect) are deprived of glucose [60]. This is because the degradation of H2O2 in cells is mediated in part by glutathione (GSH) peroxidase. However, GSH peroxidase has a high requirement for GSH, which is oxidized to GSH disulfide (GSSG) during enzyme activity. GSSG is regenerated with reducing equivalents from NADPH to GSH, which in turn is regenerated from glucose via the pentose shunt. Glucose, which is used to reduce NADP+ to NADPH, is therefore inaccessible in most malignant cells for ATP formation [58]. Overall, these findings strongly support the hypothesis that mitochondrial O2•− and H2O2 significantly contribute to the loss of glucose to the pentose shunt, leading to a decrease in ATP, enhancing cytotoxicity and metabolic oxidative stress in human cancer cells [61,62,63]. However, the subsequent NAD+ depletion and energetic crisis are dependent on the specific tumor genotype [22,64]. Moreover, mitochondria in some cancer cells exhibit increased sensitivity to hydrogen peroxide and may be less efficient at ATP generation than normal cells [62,65,66]. Such increased sensitivity of mitochondria to H2O2, with or without inefficient baseline ATP production, may also lead to decreased ATP production. These pathways of ATP depletion induced by H2O2 could be independent or more than one could be responsible for cell death in sensitive cells [62,65]. Because primary ATP generation occurs in normal cells via aerobic metabolism, and their mitochondria may not be as sensitive to H2O2 as those of some cancer cells, these cells would not be affected by pharmacological ascorbate-induced H2O2. In summary, cancer cells that largely use oxidative phosphorylation to generate ATP may be more sensitive to pharmacological ascorbate compared with cancer cells that are predominantly glycolysis-dependent [67]. Pharmacological ascorbate generates extracellular H2O2 as an essential initiator of subsequent pro-oxidative damage. However, there is evidence that catalase, by disproportionating H2O2, blocks the effects of pharmacological vitamin C [22,46,68,69]. Notably, increased levels of different NOXs at the tumor site constitute reliable prognostic markers in human gastric cancer [70,71]. NOX-derived reactive oxygen species (ROS) were shown to be a contributor to tumor development, proliferation, invasion, metastasis, and tumor-mediated angiogenesis [72]. As most tumors have decreased ability to metabolize H2O2, due to inefficiency or absence of H2O2 metabolizing enzymes, malignant cells are susceptible to pharmacologic ascorbate [73]. Moreover, H2O2-induced spatiotemporal changes in intracellular labile iron trigger the destabilization of lysosomal compartments, promoting a concomitant early response of proteins of iron homeostasis [74]. The intracellular labile iron pool (LIP) [75] is an important determinant of cellular response to oxidative stress [74,76,77]. Schoenfeld et al. showed that O2•− and H2O2, derived from increased mitochondrial metabolism, can increase pools of free, unbound cytosolic iron [22]. This pharmacological ascorbate-induced LIP increase contributes significantly to the cancer cell-selective toxicity of pharmacological ascorbate. The increased LIP in cancer cells in turn contributes to increased oxidation of ascorbate in the cell, generating further H2O2. This exacerbates the differences regarding labile iron in cancer cells compared to normal cells. Moreover, this may be due to the H2O2-mediated destruction of iron–sulfur cluster-containing proteins [78]. In addition, the increased H2O2 concentrations in the presence of elevated LIP may contribute to enhanced Fenton chemistry that generates hydroxyl radicals and causes oxidative damage [22]. Furthermore, these reactions are thought to occur preferentially on macromolecules associated with weakly chelated redox-active iron [77].
The specific cell death mechanisms triggered in tumor cells by high-dose ascorbate are not yet fully understood. Therefore, the role of ferroptosis in the ascorbate-induced death of cancer cells is unclear; presumably, depending on tumor entity and dosage, other forms of cell death also occur, such as autophagy and apoptosis [79]. Nevertheless, Wang et al. were able to demonstrate the induction of ferroptosis by high-dose ascorbate in anaplastic thyroid cancer cells [80]. Furthermore, it could be shown that ascorbate-induced accumulation of iron in combination with a simultaneous GSH reduction resulted in the enhancement of erastin-induced ferroptosis in pancreatic cancer cells [81].
3. Interplay between Ascorbate and Iron
Pharmacological ascorbate therapy affects the oxidation state of iron and increases free iron in the cytosol, which is a characteristic of various tumors [22,82,83]. Ascorbate mobilizes iron from ferritin by two separate processes: release of ferritin-bound iron by ascorbate alone or as labile iron citrate complex, which synergizes ascorbate-dependent iron mobilization and increases the maximum mobilization rate by about fivefold [84]. Under normal conditions there is a very low concentration of free iron, which is considered a source of continuous toxicity resulting in iron-ROS production. Since tumor cells are strongly dependent on iron intake for their growth and proliferation, the influx and efflux of iron through the cell membrane plays a crucial role in this process [85,86]. In contrast to iron import, most cells do not have an effective mechanism to export iron, resulting in an increase in LIP levels when the amount of iron exceeds the storage capacity thereby affecting cell survival [87]. Ferroptosis is an iron-dependent and lipid peroxidation-driven regulated cell death pathway [88,89]. In the field of redox biology, iron and other cationic metals such as copper also exacerbate oxidative stress in ferritin-containing tissue [84]. Therefore, in malignant cells, the electron-transferring properties enable labile iron to participate in the pro-oxidative reaction of ascorbate to form Asc•−, O2•−, H2O2, and OH• providing even more ferrous iron (Fe3+ + AscH– → Fe2+ + H+ + Asc•–), boosting the Fenton reaction (Fe2+ + H2O2 → Fe3+ + OH•+ OH–) and enhancing pharmacological ascorbate-induced toxicity [22,31,82]. Hydrogen peroxide forms hydroxyl radicals under the catalytic action of Fe2+, which is the basis of free radical lipid peroxidation. Hydroxyl radicals and hydroperoxides are the two most widespread ROS that affect lipids, which may compromise the integrity of lysosomal membranes during oxidative stress [90,91,92]. Lipid peroxidation is a positive feedback chain reaction driven by ROS, including superoxide peroxides and free radicals, initiating the oxidation of polyunsaturated fatty acids [91]. As labile iron was shown to be closely related to ascorbate-induced toxicity for different cell types, the interaction between iron and ascorbate inside and outside cells seems to play an opposite role [82,93,94,95]. However, if the hydroxyl radical generated outside the cell by the Fenton reaction is already reacting extracellularly, it cannot reach its intracellular targets appropriately, which strongly reduces the anticancer efficacy of ascorbate [94,95]. Consequently, the time-shifted combination of iron with pharmacological ascorbate to increase the intracellular iron toxicity via enhancing the effect of pharmacological ascorbate is promising [82,93]. However, this requires the tumor cell to have sufficient capacity for the uptake of iron. Iron can generally be categorized by the chelate in which it is presented to the cell, either as transferrin (Tf)-bound iron (TBI) or non-Tf-bound iron (NTBI), depending on the following major players: transferrin receptors (TfRs), divalent metal transporter 1 (DMT1), and ferroportin 1 (FPN1).
In view of the explanation for ascorbate-induced cytotoxicity, the accumulation of ascorbate-related co-actors in the cell and the stimulation of the respective uptake mechanisms seem to be relevant aspects for further research on pharmacological ascorbate therapy. In general, the transport mechanisms of molecules into (and out of) the cell are: (i) diffusion (passive as O2 molecules or facilitated diffusion along a concentration gradient, through a protein channel such as aquaporins (AQPs), and through ion channels); (ii) primary or secondary active transport; and (iii) vesicle-mediated transport (e.g., endocytosis or exocytosis). The relevant shuttle mechanisms for effective pharmacological ascorbate treatment and ferroptosis induction in cancer are summarized in Table 1.
Table 1. Major proteins involved in the transport of H2O2, vitamin C, and iron across the cell membrane and their expression in normal and tumor tissues.
| Protein Name | Substrate | Tissue Expression | Tumor Tissue Expression | Functionally Relevant Genetic Polymorphisms | Consequences of Genetic Variations | Association with Other Parameters | References |
|---|---|---|---|---|---|---|---|
| AQP1/3/5/8/9/11 | H2O2 | widespread, e.g., lung, kidney, pancreas | various, e.g., pancreatic cancer breast, ovarian, prostate cancer, CRC, HCC, glioblastoma | AQP9: SNP rs1516400 | associated with chemotherapy response in lung cancer patients | AQP1 expression is associated with increased DFS in CRC patients and AQP3 expression with OS in gastric cancer patients | [96,97,98,99,100,101,102,103,104,105,106,107,108] |
| AQP11: SNP rs2276415 | associated with kidney disease in type 2 diabetic patients | ||||||
| SVCT1 | vitamin C | epithelial tissue of kidney, liver, intestine, lung, skin | RCC | SNPs rs33972313 and rs11950646 | decreased vitamin C plasma concentration | - | [109,110,111,112] |
| SNPs rs659647 and rs11950646 | higher risk of follicular lymphoma | ||||||
| SVCT2 | vitamin C | widespread, e.g., CNS | various, e.g., breast cancer, melanoma, CRC, pancreatic cancer | multiple SNPs | increased vitamin C plasma concentration, increased risk of gastric cancer, follicular lymphoma, leukemia, colorectal adenoma | - | [24,113,114,115,116,117,118] |
| GLUT1/3/4 | DHA | ubiquitous, e.g., brain, placenta, prostate | widespread, e.g., CRC, HCC, prostate cancer, lymphoma, glioblastoma, lung cancer | GLUT1: SNP rs710218 | increased risk of CRC, associated with susceptibility to develop clear-cell renal carcinoma | increased expression of GLUT1 is associated with unfavorable OS and poorer DFS |
[64,119,120,121,122,123,124,125,126,127] |
| DMT1 | Fe2+ | ubiquitous, strong expression e.g., in proximal duodenum, brain, kidney, placenta | various, e.g., CRC, ovarian cancer, prostate cancer, esophageal adenocarcinoma | SNP 1254T>C | associated with Parkinson’s disease | high expression is associated with longer DFS in HCC patients | [128,129,130,131,132,133,134,135,136] |
| SNP IVS4+44C/A | associated with increased blood levels of iron, lead, and cadmium | ||||||
| TfR1/2 | Fe3+ (Tf- bound) | widespread, e.g., liver, intestine, activated immune cells | various, e.g., HCC, breast cancer, ovarian cancer, pancreatic cancer, lung cancer | multiple SNPs | associated with iron biomarkers | TfR1 expression correlates with tumor stage and is associated with a high risk of recurrence and short patient survival | [137,138,139,140,141,142,143,144,145,146] |
| SNP rs9846149 | reduced risk for gastric cancer | ||||||
| FPN | Fe2+ | liver, duodenum, placenta, bone marrow, breast, brain | reduced activity in most tumor entities, e.g., cholangiocarcinoma, breast cancer, pancreatic cancer, prostate cancer | gain of function mutations | hepcidin resistance, HH type 4B | decreased FPN expression is associated with reduced survival in breast cancer patients | [147,148,149,150,151,152,153] |
AQP: aquaporin; CNS: central nervous system; CRC: colorectal cancer; DFS: disease-free survival; DMT1: divalent metal transporter 1; FPN: ferroportin; GLUT: glucose transporter; HCC: hepatocellular carcinoma; HH: hereditary hemochromatosis; OS: overall survival; RCC: renal cell carcinoma; SNP: single nucleotide polymorphism; SVCT: sodium-dependent vitamin C transporter; Tf: transferrin; TfR: Tf receptor.
4. Aquaporins
AQPs are channel proteins from a larger family of major intrinsic membrane proteins and are widely distributed in human tissues with different localizations at cellular and subcellular levels [96,97]. Since some members of the AQP family facilitate the diffusion of H2O2, they are also named peroxiporins [154,155,156,157] and their function has been related to both volume regulation and ROS elimination [96]. The regulation of H2O2 permeation can also contribute to a resistant phenotype of tumors and peroxiporin activity could modify the cellular antioxidative defense system, thereby contributing to oxidative stress resistance [158]. AQP1, AQP3, AQP5, AQP8, AQP9, and AQP11 expression was reported in human tumors, and in some cases correlated with tumor grade, opening new diagnostic and therapeutic opportunities [56,101,159,160,161,162,163,164,165,166,167,168]. Therefore, peroxiporin expression was suggested to be an important determinant modulating cancer cell susceptibility to therapeutic H2O2 formation induced by pharmacological ascorbate [161,169]. H2O2 plasma membrane permeability was demonstrated to have significant variability across cell lines [170]. Although intracellular H2O2 concentration plays a key role in cellular susceptibility to adjuvant ascorbate therapy (Table 1), its overall contribution to the therapeutic effectivity of ascorbate is not clear [161].
5. Ascorbate Transporters
The entrance of vitamin C into the cell is determined by specific transporters. These belong to a family of nucleobase transporters and are highly conserved through evolution [110,171]. Human sodium-dependent vitamin C transporter (SVCT) 1 is encoded by the solute carrier family 23 member 1 (SLC23A1) gene that is mapped on chromosome 5 yielding a 598 amino acid polypeptide (Table 1). SVCT2, as a SLC23A2 gene product from chromosome 20, is a 650 amino acid polypeptide [172]. Both can actively transport ascorbic acid against gradients by coupling its entry with sodium influx into the cell, thus maintaining the sodium gradient throughout the plasma membrane, which is provided by Na+/K+-ATPase [173]. Although plasma membrane SVCT2 is a Na+-dependent co-transporter, it also exhibits absolute dependence on Ca2+ or Mg2+. In contrast, intracellular SVCT2 is exposed to high ascorbic acid and low Na+, Ca2+, and Mg2+ and is a low-affinity transporter that lacks Na+ cooperativity [173]. SVCT1 is situated in the brush-border membrane of absorptive epithelial tissue of, e.g., kidney, intestine, liver, lung, and skin [109,110]. In humans, no loss of SLC23A1 has been described to date. Different single nucleotide polymorphisms (SNPs) have been shown to weaken ascorbate transport and to reduce plasma levels with a trend toward a higher cancer risk for SLC23A1 variants [111,174,175,176,177]. Heterogenic results were reported for gene expression control and there is also limited information regarding posttranslational modifications and the factors influencing cellular localization [60,178,179,180,181]. In cancer patients, studies evaluating SVTC1 tissue distribution between normal and malignant cells and also observations of SVTC1 expression under ascorbate or standard chemo-radiation regimens have not been conducted. SVCT2 is widely distributed and is therefore the predominant tissue transporter for vitamin C in most tissues and in blood cells [24,113]. A short isoform of SVCT2, naturally occurring in humans through alternative splicing, is unable to transport ascorbate and has the ability to partially inhibit SVCT1 [182,183]. Pathological circumstances associated with liver metabolic or oxidative stress may affect the expression of vitamin C transporters in different ways [178]. SVCT2 is expressed in Lewis lung tumors grown in ascorbate-dependent mice [184]. SVCT2 protein levels varied over time following a single high-dose ascorbate injection, but their association with tumor ascorbate levels was complex [184]. In human breast cancer cells, SVCT2 mRNA levels differed significantly between cell lines [185]. Cellular and subcellular localization of SVCT2 determines its transport activity and depends on different cell types, ascorbate concentration as well as intracellular Na+ and K+ concentrations [186,187,188,189]. Expression of SVCT2 in human neuroblastoma tissue was confirmed by immunofluorescence [190]. SVCT2 protein levels in breast cancer cells were predictive for ascorbate uptake and cellular sensitivity to ascorbate cytotoxicity [110]. This was confirmed by overexpression and gene knockdown in vitro [115]. Interestingly, SVCT2 expression was absent or weak in normal tissues but strongly detected in tumor samples obtained from breast cancer patients, suggesting that functional SVCT2 sensitizes breast cancer cells to autophagic damage by increasing the ascorbate concentration and intracellular ROS production. Therefore, the presence of SVCT2 in breast cancer may act as a predictor for the effectiveness of ascorbate treatment [115]. SCVT2 was overexpressed in the mitochondria of breast cancer cells, but only marginally presented on the plasma membrane [116]. Augmented expression of mitochondrial SVCT2 appears to be a common hallmark across all human cancers and might have implications for the survival capacity of cancer cells in pro-oxidant environments [116,191]. In addition, the analysis of numerous tissue microarrays contained in the Human Protein Atlas reveals the intracellular expression of SVCT2 in different cancer tissues [116]. Moreover, it was shown that resistance to cetuximab in human colon cancer patients with mutated Kirsten rat sarcoma viral oncogene homologue (KRAS) can be bypassed by ascorbate in an SVCT2-dependent manner. For the treatment of KRAS-mutated colon cancer, the SVCT2 expression may act as a potent marker for ascorbate co-treatment with cetuximab [28]. In addition, in low SVCT2-expressing cells, high-dose ascorbate (>1 mM) showed anti-cancer effects, but low-dose (<10 μM) (as defined by the authors for both incubation procedures) treatment induced cell proliferation in colorectal cancer cell lines so that insufficient uptake of ascorbate in low SVCT2-expressing cancer cell lines cannot generate sufficient ROS to kill the cancer cells [192]. Supplementation of Mg2+ enhanced the anticancer effect of ascorbate by inhibiting the hormetic response at a low dose, also providing a more pronounced anticancer response in cells with low SVCT2 expression compared to ascorbate treatment alone [193]. In hepatocellular carcinoma (HCC), the synergistic effect of ascorbate and sorafenib was shown in patients without elucidating the role of vitamin C transporters [194]. In cholangiocarcinoma cell lines, ascorbate worked synergistically with cisplatin [195]. Thereby, SVCT2 expression was inversely correlated with the half-maximal inhibitory concentration (IC50) values of ascorbate [196]. Furthermore, SVCT2 knockdown endowed cholangiocarcinoma cells with treatment resistance, and the SVCT2 expression level was suggested as a positive outcome predictor for ascorbate treatment in this tumor entity [195]. In the liver, a close relationship between B-cell lymphoma 2 (BCL2) and SLC23A2 with several other genes was revealed to play an important role in the expression levels of these genes [197]. In line, a decreased ascorbate uptake mediated by SLC2A3 (alt. GLUT3) promotes leukemia progression and impedes ten-eleven translocation 2 (TET2) restoration [198]. High expression levels of SVCT2 were related to a good prognosis in patients with pancreatic adenocarcinoma [117]. Otherwise, only a limited association between ascorbate concentrations and its transporters was identified in renal cell carcinoma (RCC) cells and clinical samples [111]. Positron emission tomography (PET) imaging and tissue distribution analysis showed that cancer cells with high SVCT2 expression enhanced the accumulation of labeled ascorbate derivatives in mice after tumor formation. Correlations of SLC23A2 gene polymorphisms related to ascorbate levels and disease risks depend on tumor entity and study population [175,199,200,201]. Two SNPs related to increased vitamin C plasma concentrations and several others were identified as posing a high risk of gastric cancer, follicular lymphoma, chronic lymphocytic leukemia, colorectal cancer (CRC), or head and neck cancer [175,176,177,199,201,202].
This entry is adapted from the peer-reviewed paper 10.3390/antiox12040916
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