High-dose vitamin C may not attack cancer cells simply by acting as an antioxidant. This review argues that membrane transport proteins could decide whether ascorbate, hydrogen peroxide, and iron enter the tumor cell—and whether oxidative damage becomes lethal.

For 2020, cancer incidence across thirty-six cancer types in one hundred eighty-five countries was about nineteen point three million, with nearly ten million deaths. By 2040, twenty-eight point four million new cancer cases are expected, a forty-seven percent increase from 2020.

Small cell lung cancer, pancreatic ductal adenocarcinoma, advanced ovarian cancer, triple-negative breast cancer, and glioblastoma are highly aggressive solid tumors with invasive phenotypes and treatment resistance. For these tumor entities, the review identifies an urgent need for novel treatment approaches, and presents vitamin C as both an essential micronutrient and a bioactive substance acting as a prodrug.

The predominant mechanism underlying the anticancer activity of parenteral pharmacological vitamin C is based on its ability to act as a prodrug, through preferential steady-state formation of the ascorbate free radical and hydrogen peroxide in the extracellular space.

The review therefore distinguishes extracellular formation of reactive species from their limited formation in blood, a distinction central to pharmacological ascorbate treatment. When cells encounter an external source of hydrogen peroxide, rapid intracellular degradation helps create a gradient across the plasma membrane and other subcellular membranes.

The steady-state concentration of hydrogen peroxide in intact cells was calculated to be about one to ten nanomolar, while concentrations above one hundred nanomolar can cause intracellular accumulation, biomolecule destruction, disrupted redox signaling, growth arrest, and cell death.

Hydrogen peroxide uptake and distribution therefore follow gradients between extracellular and intracellular spaces and between subcellular compartments. Hydrogen peroxide accumulation can increase toxicity in sensitive cells and correlate with a decline in intracellular ATP, while DNA single-strand breaks can increase PARP activity and consume intracellular NAD plus, contributing to ATP depletion.

In cancer cells relying on anaerobic metabolism, glucose is diverted toward regeneration of glutathione, making it inaccessible for ATP formation. The text also cautions that the later NAD plus depletion and energetic crisis depend on the specific tumor genotype.

Normal cells may be less affected because primary ATP generation uses aerobic metabolism and their mitochondria may be less sensitive to hydrogen peroxide than those of some cancer cells. Cancer cells that largely use oxidative phosphorylation may therefore be more sensitive to pharmacological ascorbate than cancer cells that are predominantly glycolysis-dependent.

Catalase can block pharmacological vitamin C effects by disproportionating hydrogen peroxide, while many tumors have decreased ability to metabolize hydrogen peroxide. The specific cell-death mechanisms triggered in tumor cells by high-dose ascorbate are not yet fully understood, so the role of ferroptosis remains unclear.

Depending on tumor entity and dosage, autophagy and apoptosis may also occur. Even so, high-dose ascorbate was shown to induce ferroptosis in anaplastic thyroid cancer cells, and ascorbate-driven iron accumulation with simultaneous GSH reduction enhanced erastin-induced ferroptosis in pancreatic cancer cells.

Pharmacological ascorbate affects iron’s oxidation state and increases free iron in the cytosol, a characteristic of various tumors. Ascorbate mobilizes iron from ferritin either directly or as a labile iron citrate complex, which increases the maximum mobilization rate by about fivefold.

Because tumor cells strongly depend on iron intake, iron influx and efflux through the cell membrane play a crucial role. Ferroptosis is an iron-dependent, lipid-peroxidation-driven regulated cell-death pathway. The review identifies accumulation of ascorbate-related co-actors in the cell and stimulation of their uptake mechanisms as relevant areas for further research on pharmacological ascorbate therapy.

Molecules enter or leave cells through diffusion, active transport, or vesicle-mediated transport. The relevant shuttle mechanisms for effective pharmacological ascorbate treatment and ferroptosis induction in cancer are summarized in Table 1.

Aquaporins are channel proteins distributed across human tissues, and some aquaporin family members facilitate hydrogen peroxide diffusion; these are also called peroxiporins. Peroxiporin activity can modify the cellular antioxidative defense system and contribute to oxidative stress resistance, potentially producing a resistant tumor phenotype.

AQP1, AQP3, AQP5, AQP8, AQP9, and AQP11 expression has been reported in human tumors, sometimes correlating with tumor grade. Peroxiporin expression was therefore suggested as an important determinant of cancer-cell susceptibility to therapeutic hydrogen peroxide formation induced by pharmacological ascorbate.

The entrance of vitamin C into the cell is determined by specific transporters belonging to a conserved family of nucleobase transporters. SVCT1 is encoded by the SLC23A1 gene on chromosome five, while SVCT2 is the SLC23A2 gene product from chromosome twenty.

Both transporters actively move ascorbic acid against gradients by coupling entry to sodium influx. Cells take up ascorbate through SVCTs, while dehydroascorbic acid accumulates through facilitated diffusion via GLUTs after ascorbate oxidation.

GLUT1, GLUT3, and GLUT4 specifically mediate dehydroascorbic acid transport and subsequent accumulation of ascorbate. Hypoxia-inducible factor one is associated with high levels of glucose transporters such as GLUT1 in malignancies. Human colorectal cancer cells with KRAS or BRAF mutations were selectively killed in vitro by high vitamin C levels because of increased dehydroascorbic acid uptake through GLUT1.

The review concludes that the role of GLUT-mediated dehydroascorbic acid uptake in ascorbate-induced cytotoxicity appears only partially relevant and remains to be fully elucidated. Transferrin receptor one is overexpressed in many cancer-cell types, often at levels many times higher than in normal cells, and this correlates with advanced tumor stage and poor prognosis.

Transferrin receptor one binds transferrin and forms a ligand-receptor complex that is constitutively internalized through clathrin-mediated endocytosis. In many cancers, transferrin-receptor expression is significantly dysregulated and iron uptake is abnormal.

Transferrin receptor one has been proposed as a prognostic marker for many tumors, although its prognostic role may be tumor-specific. DMT1 belongs to the SLC11 family of metal-ion transporters and uses the hydrogen electrochemical gradient. It accepts a broad range of transition metal ions, with ferrous iron transported at high affinity.

DMT1 supports intestinal absorption of free ferrous iron and transferrin-associated endosomal ferrous-iron transport in erythroid precursors and many other cell types. DMT1 is highly expressed in colorectal and ovarian cancers, and its overexpression promoted ovarian-tumor progression.

FPN1 exports iron into the extracellular space, where ferrous iron is re-oxidized to ferric iron by ferroxidases such as ceruloplasmin or hephaestin. FPN1 is the major basolateral iron exporter in epithelial cells and is regulated post-translationally by hepcidin.

Hepcidin binding causes FPN1 ubiquitination, internalization, and degradation, controlling the amount of iron released into blood. In cancer cells, downregulated FPN1 activity increases the iron pool, while stimulating FPN1 reduces cancer-cell growth and proliferation through cellular iron deprivation.

Table one maps key membrane transport proteins to their substrates, tissue distributions, tumor-tissue expression, and clinically relevant genetic variants. It identifies aquaporins as channels that can facilitate hydrogen peroxide movement, while SVCT1 and SVCT2 transport vitamin C; the table also links specific SNPs with chemotherapy response, kidney disease, vitamin C plasma concentration, and cancer risk.

This matters because transporter expression and variation may shape how cells handle ascorbate and reactive oxygen species during tumor biology and therapy. Table one continuation catalogs four transport systems—GLUT one, three, and four; DMT1; TfR1/2; and FPN—alongside their substrates, tissue and tumor expression, relevant polymorphisms, genetic consequences, and clinical associations.

The table links GLUT1 variation to colorectal cancer risk and poorer overall and disease-free survival, while describing associations involving iron transporters with Parkinson’s disease, iron biomarkers, tumor stage, recurrence, and survival. This matters because it connects nutrient and metal transport with tumor biology and patient outcomes.

Pharmacologic ascorbate treatment has had anticancer potential reported for over forty years, and preclinical investigations plus a few small early-phase clinical trials have shown feasibility, selective toxicity, tolerability, and potential efficacy for different tumor entities.

However, final evidence for efficacy in tumor patients is not yet conclusive. Although phase one and phase two a studies have produced promising results, proven results from larger randomized patient cohorts, such as phase three clinical trials, are still lacking.

The review also states that ascorbate contributes to improved patient quality of life in addition to its antiproliferative effect on tumor cells. The review proposes SVCT1 and SVCT2, GLUT1 and GLUT3, transferrin receptors and DMT1, FPN1, and aquaporins as relevant shuttle systems for effective pharmacological ascorbate treatment and ferroptosis induction in cancer.

Cell-model data indicate that ascorbate forms the ascorbate free radical and hydrogen peroxide and reduces intracellular unbound iron, which in turn generates a greater amount of reactive oxygen species. Tumor cells exhibit increased iron metabolism, elevated iron uptake, and diminished iron release, contributing to increased labile iron pools.

Figure one maps how tumor cells handle ascorbate, iron, and hydrogen peroxide at the plasma membrane. Ascorbate enters through SVCTs, while DHA is associated with GLUT transport; iron moves through transferrin receptors, FPN1, and DMTs, and hydrogen peroxide can enter through AQP channels.

Inside the cell, these pathways connect iron redox chemistry with AFR and hydroxyl-radical formation, producing ROS linked to lipid peroxidation and ferroptosis. Intracellularly, dehydroascorbic acid is oxidized by ferric iron to form the ascorbate free radical and increase cellular oxidative stress.

Extracellularly formed hydrogen peroxide enters through aquaporin membrane channels, where ferrous iron catalyzes hydroxyl-radical formation through the Fenton reaction. These reactions generate further reactive oxygen species, lipid peroxidation, and ultimately cell death.

Iron enters through transferrin receptors by endocytosis for transferrin-bound ferric iron, or through DMT1 and other divalent iron transporters for unbound ferrous iron, while FPN1 exports iron. Figure two contrasts physiological tissue with cancer across extracellular iron and ascorbate measures, and maps the transporters handling ascorbate, dehydroascorbic acid, iron, and hydrogen peroxide.

It highlights that cancer-associated conditions include lower listed ferritin, hemoglobin, ascorbate, and transferrin saturation values, alongside prominent formation of ascorbate free radicals and hydroxyl radicals. The authors use this framework to explain why transporter expression, labile iron, and pharmacologic ascorbate exposure can influence tumor-cell damage.

Some publications propose that ascorbate can promote tumor-cell proliferation and advise against high-dose ascorbate therapy, findings that contradict the vast majority of in vitro and in vivo studies. The review explains that one study compared orally achievable plasma concentrations with vitamin C deficiency, while another partly used dehydroascorbic acid rather than ascorbate and found no difference at five hundred micromolar compared with physiological concentrations.

Clinical findings associate vitamin C deficiency with poorer prognosis in cancer patients. Tumor cells have limited capacity to regulate labile iron pools that react with pharmacological ascorbate or hydrogen peroxide and contribute to additional reactive oxygen species formation.

Accumulation of unbound cellular iron and elevated reactive oxygen species cause excessive lipid peroxidation, limit antioxidant resources, and lead to ferroptotic cell death. The review emphasizes that availability and functionality of uptake systems on the tumor-cell surface are important for achieving sufficient ascorbate and iron levels to induce antiproliferative effects.

It remains unknown whether coordinated interaction among individual uptake mechanisms is prevalent or can be therapeutically initiated. Chemotherapeutic agents and irradiation should be evaluated for their effects on the expression and functionality of membrane uptake systems in vitro and in animal models.

Multidrug-resistance extrusion systems on the cell surface should also be considered because chemotherapy can induce them as a protection against cytotoxic agents and as a cellular survival strategy. The review concludes that a nuanced understanding of the interplay among ascorbate, hydrogen peroxide transporters, and iron shuttle systems is urgently needed to induce sufficient ferroptosis and identify tumors sensitive to ascorbate therapy.

The review’s central message is that pharmacological ascorbate may work best when tumor-specific transport systems bring in ascorbate or its oxidized form, hydrogen peroxide, and iron while limiting iron export. These gatekeepers could guide biomarkers and treatment optimization, but clinical efficacy remains unproven.