Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine

Abstract

Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2′-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFNinducing cellular response. This synergistic effect is likely the result of both passive DNA demethylation by DNMTi and active conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes at LTR regions of ERVs, because vitamin C acts as a cofactor for TET proteins. In addition, TET2 knockout reduces the synergy between the two compounds. Furthermore, we show that many patients with hematological neoplasia are markedly vitamin C deficient. Thus, our data suggest that correction of vitamin C deficiency in patients with hematological and other cancers may improve responses to epigenetic therapy with DNMTis.

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

“…Others recently showed that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH (Yun et al, 2015). Vitamin C treatment of various cancer cell lines also enhances the viral mimicry response to DNA methyltransferase inhibitors such as 5-azacytidine (Liu et al, 2016). Given the diversity of α-KG and Fe 2+ -dependent enzymes that utilize vitamin C as a co-factor (including prolylhydroxylases, jumonji histone demethylases, and TET enzymes) (Young et al, 2015), the mechanistic basis for vitamin C action could well depend on the type of cancer and/or its dependence on specific dioxygenases.…”

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

“…In support of this proposition, it has been found that a high proportion of cancer patients are actually deficient in vitamin C [84]. Interestingly, in vitro modeling experiments have shown that vitamin C amplifies the anticancer effects of decitabine, a drug commonly used in treatment of hematological malignancies and well-described driver of DNA demethylation [85]. It will be important to explore this initial work with mechanistic understanding of how future science group Special Report Hore vitamin C (and decitabine) interact with cancer cells, and ultimately, advanced testing in a clinical setting where ascorbate delivery and pharmacokinetics can be effectively controlled.…”

High Doses of Vitamin C and Leukemia: In Vitro Update

“…The reduction of plasma Vitamin C levels in leukemia, as predicted by Stone, is due to an increased uptake and utilization by the actively proliferating leukocytes, leading to tissue biochemical scurvy and consequent increased tendency to bleeding and infections, which are the hallmark of this pathological condition [9,10]. Interestingly, low plasma levels of Vitamin C, have been, very recently, found in around 30% of cases of Non-Hodgkin Lymphoma (NHL), particularly in patients with high bulk disease [11].…”