Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia

Abstract

Background Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions. Methods Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated. Results Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells. Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL. Conclusion These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.

High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer

“…Similarly, resistance to BRAFV600 inhibitor vemurafenib was also abrogated by VitC in melanoma in vivo [ 123 ]. Recent findings reinforce the promising synergistic effects of VitC with kinase inhibitors such as BRAFV600 inhibitor PLX4032 in thyroid cancer in vivo [ 64 ] and with BTK inhibitor ibrutinib and PI3K inhibitor idelalisib in chronic lymphocytic leukemia (CLL) patient-derived cells [ 104 ].…”

“…sorafenib, gefitinib, vemurafenib) [ 109 , 116 , 123 ], mitochondrial inhibitors (i.e. doxycycline, venetoclax, oligomycin A, metformin) [ 104 , 106 , 107 ], poly ADP ribose polymerase (PARP) inhibitors [ 193 ] and glycolysis inhibitors [ 194 ].…”

“…Likewise, emerging anti-cancer compounds targeting telomerases, mitochondrial activity or glycolysis also synergize with high-dose VitC. For instance, telomerase inhibitor triethylenetetramine (TETA) in the treatment of breast cancer [ 122 ], glycolysis inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO) in NSCLC cells [ 194 ], respiratory chain complex I inhibitor metformin, ATP synthase inhibitor oligomycin A and Bcl-2 inhibitor venetoclax in CLL patient-derived cells [ 104 ].…”

Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer

“…Understanding the pharmacokinetics of ascorbate distribution into the tumour cells is vital for the planning of clinical trials and support for novel ascorbate treatments [59,66], as oral and intravenous administration result in different plasma pharmacokinetics [76]. A number of case studies and clinical trials on cancer patients have described that ascorbic acid at high doses, alone, or in combination with chemotherapies improves the quality of life with less toxicity [128,129]. Vitamin C hinders cancer progression by targeting different vulnerable nodes such as HIF, GLUT1 [46,59,66], and TET [130,131].…”

Restoration of the immune function as a complementary strategy to treat Chronic Lymphocytic Leukemia effectively

“…Ascorbic acid is a pro-oxidant agent that has shown to overcome the protective effect of the microenvironment. It can potentiate the effects of ibrutinib, idelalisib and venetoclax in vitro and it was able to reduce the viability of CD40L/IL-4-stimulated CLL cells [97].…”