Vitamin C as a Modulator of the Response to Cancer Therapy

Abstract

Ascorbic acid (vitamin C) has been gaining attention as a potential treatment for human malignancies. Various experimental studies have shown the ability of pharmacological doses of vitamin C alone or in combinations with clinically used drugs to exert beneficial effects in various models of human cancers. Cytotoxicity of high doses of vitamin C in cancer cells appears to be related to excessive reactive oxygen species generation and the resulting suppression of the energy production via glycolysis. A hallmark of cancer cells is a strongly upregulated aerobic glycolysis, which elevates its relative importance as a source of ATP (Adenosine 5′-triphosphate). Aerobic glycolysis is maintained by a highly increased uptake of glucose, which is made possible by the upregulated expression of its transporters, such as GLUT-1, GLUT-3, and GLUT-4. These proteins can also transport the oxidized form of vitamin C, dehydroascorbate, permitting its preferential uptake by cancer cells with the subsequent depletion of critical cellular reducers as a result of ascorbate formation. Ascorbate also has a potential to affect other aspects of cancer cell metabolism due to its ability to promote reduction of iron(III) to iron(II) in numerous cellular metalloenzymes. Among iron-dependent dioxygenases, important targets for stimulation by vitamin C in cancer include prolyl hydroxylases targeting the hypoxia-inducible factors HIF-1/HIF-2 and histone and DNA demethylases. Altered metabolism of cancer cells by vitamin C can be beneficial by itself and promote activity of specific drugs.

Vitamin C increases DNA breaks and suppresses DNA damage-independent activation of ATM by bleomycin

“…This hypersensitivity to Asc has been linked to a heightened uptake of DHA by cancer cells due to their frequent overexpression of the DHA-transporting GLUT1, which is linked to specific oncogenic changes and the general increased dependency of transformed cells on aerobic glycolysis. Asc overloading and the resulting metabolic stress can also sensitize cancer cells to killing by some chemotherapeutic agents [17,34,53]. Our studies also found a stronger cytotoxicity of BLM in cells that were preincubated with DHA, however, this effect was unlikely linked to Asc overloading and the resulting metabolic/ energy stress.…”

Mechanisms and Applications of the Anti-cancer Effect of Pharmacological Ascorbic Acid in Cervical Cancer Cells

“…In addition, intravenously administered ascorbate also appears to affect DNA demethylation through the Tet2 enzyme, another Fe 2+ -2-oxoglutarate-dependent dioxygenase (7,47). Under homeostatic conditions, L-AA regulates the balance between self-renewal, differentiation, and cell death of hematopoietic stem cells and pluripotent progenitors by promoting Tet2 activity (4,10,47). Thus, L-AA may serve as an ROS modulator, a hypoxia stimulator, an epigenetic editor, and an enzyme cofactor during cancer therapy.…”

L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus

“…Moreover, L-AA inhibits the growth and metastasis of various types of cancers, including melanoma [14], breast cancer [15], gastric cancer [16], colorectal cancer [17], pancreatic cancer [18], and leukemia [19]. Many studies have reported that the L-AA concentration in the plasma of cancer patients (10~30 µM) is lower than that of healthy controls (50~100 µM) [20][21][22][23][24]. In adults, the recommended daily dose of L-AA is about 75-90 mg in USA [25], but administration of high-dose L-AA (8 g/day) is known to be effective in preventing common cold [26].…”