Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity

Abstract

Vitamin C (VC) is an essential nutrient that is vital for maintaining cellular physiology. Interestingly, it functions as either an antioxidant or a pro-oxidant, depending on the concentration used. At high-doses, VC selectively targets various cancer cell types through its pro-oxidant action, while at low-doses, VC enhances anti-tumor immunity by acting as an antioxidant. This versatility makes VC a promising anti-tumor agent for both standalone and combination therapies. Tumors consist of diverse cancer cell subtypes with distinct phenotypic and functional characteristics. In particular, cancer stem cells (CSCs), which are self-renewing multi-potent cells, are responsible for tumor recurrence, metastasis, chemoresistance, and heightened mortality. CSCs are often associated with the epithelial-mesenchymal transition (EMT), which confers increased motility and invasive capabilities that are characteristic of malignant and drug-resistant cells. Thus, eradicating CSC populations is crucial and has led to extensive efforts aimed at identifying medicines that can target them. Recent studies suggest that VC can selectively target CSCs via epigenetic and metabolic pathways in various cancers. Here, we highlight recent progress that has been made in understanding how VC effectively targets CSC evolution, providing a rationale for the use of VC either alone or in combination with other treatments to improve outcomes.

Keywords: cancer stem cells; epithelial–mesenchymal transition; vitamin C.

Figure 1

Physiological and anti-cancer mechanisms of vitamin C activity. (A) Physiological vitamin C (VC) exists largely in its reduced (ascorbic acid (AA)) or oxidized (dehydroascorbic acid (DHA)) forms, determined by either the gain or loss of two electrons and two hydrogens (reduction: +2e⁻ +2H⁺; oxidation: −2e⁻ −2H⁺). (B) Pharmacological VC can induce cancer cell death through two complementary mechanisms that elevate oxidative stress. Following VC treatment, hydrogen peroxide (H₂O₂) is produced in the extracellular environment by AA oxidation via Fenton chemistry that is facilitated by the presence of labile ferric iron (Fe³⁺) that enters cancer cells from the tumor microenvironment through either aquaporins or passive diffusion. VC enters cells through sodium-dependent vitamin C transporters (mainly SVCT2) when it is in its reduced form (AA), or via glucose transporters (mainly GLUT1) when it is in its oxidized form (DHA). Once inside the cell, dehydroascorbic acid (DHA) is rapidly converted to ascorbic acid (AA) through the action of the reducing agent glutathione (GSH). This process depletes the intracellular glutathione, resulting in elevated levels of intracellular H₂O₂ and several detrimental effects, including DNA damage, lipid peroxidation, and protein oxidation. In particular, DNA damage triggers the activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), which depletes cellular NAD⁺ levels. This depletion, in turn, inhibits the activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and glycolysis in cancer cells, resulting in decreased ATP production and cell death. (C) VC plays a pivotal role in numerous biological processes by serving as a cofactor for Fe²⁺ and alpha-ketoglutarate-dependent dioxygenases (Fe²⁺/α-KGDDs). These enzymes encompass a range of proteins, including collagen prolyl hydroxylases (CP4H), JmjC histone demethylases (JHDMs), ten–eleven translocation (TET) DNA hydroxylases, and hypoxia-inducible factor (HIF) hydroxylases (such as proline hydroxylase domain proteins (PHDs), and asparagine hydroxylase (factor-inhibiting HIF [FIH])). These enzymes have diverse functions, such as regulating collagen synthesis to maintain skin tissue and extracellular matrix (ECM) integrity as well as to facilitate efficient wound healing. They can also promote histone and DNA demethylation, thereby enhancing induced pluripotent stem cell (iPSC) reprogramming and suppressing leukemia progression. Furthermore, they can modulate various responses under low-oxygen conditions (hypoxia). This figure was created using BioRender, with modifications inspired by [42,43,44].

Figure 2

The influence of CSCs on anti-cancer treatment efficacy. Cancer stem cells (CSCs) represent a minority subpopulation within the overall tumor mass that displays remarkable resistance to chemotherapy and significantly contributes to tumor recurrence. Conventional treatments typically lead to a temporary decrease in tumor size by eliminating non-stem cancer cells (differentiated cancer cells). However, residual CSCs can give rise to recurrent tumors, and the initiation of metastasis is facilitated by the establishment of secondary cell colonies in distant organs. The adoption of CSC-specific inhibitors as cancer treatments has the potential to mitigate therapy resistance, lower the risk of relapse, and hinder metastasis, all while curtailing the stem cell properties of these cells. This figure was created using BioRender, with modifications inspired by [25].

Figure 3

Impact of vitamin C on CSC heterogeneity and plasticity. Cancer cells exhibit intratumoral diversity via their ability to transition back and forth between CSC and non-CSC/differentiated states. Epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) are two fundamental processes that mediate the reversible conversion of epithelial cells into mesenchymal cells and vice versa, which plays a crucial role in cancer cell plasticity and metastasis. These dynamic transitions are modulated by various factors, including epigenetic, metabolic, and genetic alterations within tumor cells, as well as by changes in the tumor-immune microenvironment. Additionally, CSCs are known to undergo an epithelial-to-mesenchymal transition (EMT), often adopting an intermediate EMT state. This transition is influenced by epigenetic modifications, metabolic reprogramming to shift from glycolysis to mitochondrial oxidative phosphorylation (mtOXPHOS), genetic mutations, and changes in the ways genes are activated or silenced in cancer cells. Moreover, signals emanating from the tumor microenvironment, such as growth factors, cytokines, the presence of cancer-associated fibroblasts (CAFs) or tumor-associated macrophages (TAMs), and hypoxia, also play a role in this transition. Vitamin C (VC) has been shown to regulate epigenetic and metabolic reprogramming and EMT marker gene expression, thereby impeding malignant CSC evolution. This figure was created using BioRender.