Unveiling vitamin C: A new hope in the treatment of diffuse large B‑cell lymphoma (Review)

Abstract

Lymphoma is a malignancy of the immune system, which originates from lymphatic tissues and lymph nodes. Diffuse large B‑cell lymphoma (DLBCL) is a common type of non‑Hodgkin lymphoma, occurring in 30‑40% of all cases, which has persistent clinical challenges. The treatment of DLBCL is challenging due to its diverse genetic and biological characteristics and complex clinical physiology. Despite advancements in overall prognosis, 20‑25% of patients continue to experience relapse and 10‑15% of patients experience refractory disease. Vitamin C is a water‑soluble vitamin with antioxidant properties and notable pharmacological activity, with potential applications in cancer therapy. Pharmacological doses of vitamin C (1‑4 g/kg) can induce apoptosis in malignant cells by inhibiting and/or reversing gene mutations that are associated with hematological malignancies. For example, 10‑25% of patients with myeloid malignancies have tet methylcytosine dioxygenase 2 (TET2) gene mutations and vitamin C can regulate blood stem cell frequency and leukemia production by enhancing TET2 function. Consequently, pharmacological doses of vitamin C can inhibit the development and progression of hematological malignancies. Therefore, the present review aimed to investigate the role of vitamin C in the pathophysiology and treatment of DLBCL, whilst highlighting the potential challenges and future perspectives.

Keywords: ascorbic acid; diffuse large B‑cell lymphoma; tumor microenvironment; vitamin C.

Figure 1

Structure, absorption and transport distribution of vitamin C in vivo. (A) Chemical structure of AA. (B) Vitamin C has two active forms in the body; AA and DHA. The two enol hydroxyl groups on carbon atoms 2 and 3 of AA are dissociated to release H⁺, which oxidizes AA to form DHA. The oxidized DHA can be reduced to AA by GSH. (C) Absorption of AA and DHA. AA is transported in the intestine and absorbed into epithelial cells via SVCT1; however, the mechanism of AA transport into the blood is yet to be fully elucidated. DHA may diffuse into epithelial cells via GLUT1 or GLUT3. Once inside the cell, DHA is either converted into apoptosis-associated speck-like protein containing a caspase recruitment domain or transported into the bloodstream by GLUT1 and GLUT2, which are located in the basolateral membrane. This process maintains a low intracellular DHA concentration, which facilitates further DHA uptake. (D) Vitamin C is distributed to various organs via SVCT2. AA, ascorbic acid; DHA, dehydroascorbic acid; GSH, glutathione; GSSG, GSH disulfide; SVCT, sodium-dependent vitamin C transporter; GLUT, glucose transporter.

Figure 2

Mechanisms of vitamin C that promote oxidation and tumor cell apoptosis in hypoxic environments. (A) Pharmacological doses of vitamin C (1-4 g/kg) increase the oxidative stress in tumor cells, and thereby increase cytotoxicity. The conversion of DHA to vitamin C in cells leads to the consumption of GSH. Additionally, vitamin C promotes the reaction between Fe³⁺ and Fe²⁺, which increases the consumption of ATP and the production of ROS. Vitamin C can also upregulate the expression of BAX and inhibit the expression of BCL2. (B) Under aerobic conditions, HIF-1α can be hydroxylated by PHD, resulting in ubiquitination after pVHL binds to HIF-1α. In addition, HIF-α is inhibited by the factor FIH, thereby preventing HIF-α from binding to the co-activator protein p300/CBP. (C) Under hypoxia, the activity of PHD and FIH is limited by substrates (for example, oxygen and α-ketoglutaric acid), leading to the rapid aggregation, nuclear translocation and dimerization of HIF-1α with HIF-1β, which promotes tumor growth. In DLBCL, pharmacological doses of vitamin C (1-4 g/kg) can upregulate the expression of wild-type p53, and compete with p300, which inhibits the transcriptional activity of HIF-1α. p53 protein also induces HIF-1α degradation and promotes apoptosis. AA, ascorbic acid; DHA, dehydroascorbic acid; GSH, glutathione; GSSG, glutathione disulfide; SVCT, sodium-dependent vitamin C transporter; GLUT, glucose transporter; ROS, reactive oxygen species; HIF-1α, hypoxia-inducible factor-1α; PHD, prolyl hydroxylase; pVHL, von Hippel-Lindau protein; FIH, asparagine hydroxylation of HIF-1; CBP, cAMP-response element binding protein; DLBCL, diffuse large B-cell lymphoma; E3, E3 ubiquitin ligase.

Figure 3

Composition of the tumor microenvironment and the role of individual immune cells. Surrounding immune cells (myeloid and lymphoid cells), fibroblasts, blood vessels, extracellular matrix and signaling molecules (such as CXCL12 and IL-6) compose the TME. Furthermore, vitamin C serves a multifaceted role in regulating elements within the TME. TME, tumor microenvironment; DCs, dendritic cells; CAF, cancer-associated fibroblast; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; FASL, Fas ligand; MHC, major histocompatibility complex; Treg, immunoregulatory T cell; MDSC, myeloid-derived suppressor cell; NK, natural killer; TAMs, tumor-associated macrophages; TILs, tumor-infiltrating lymphocytes; CCL2, C-C motif chemokine ligand 2; CCL5, C-C motif chemokine ligand 5; CXCL8, C-X-C motif chemokine ligand 8; CXCL12, C-X-C motif chemokine ligand 12; CHI3L1, chitinase 3 like 1; C3a, complement component 3a.