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

Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):10238-44. doi: 10.1073/pnas.1612262113. Epub 2016 Aug 29.

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 IFN-inducing 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.

Keywords: 5-hydroxymethylcytosine; DNA methyltransferase inhibitor; endogenous retrovirus; epigenetic therapy; vitamin C.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Ascorbic Acid / administration & dosage*
  • Ascorbic Acid Deficiency / complications
  • Ascorbic Acid Deficiency / drug therapy
  • Ascorbic Acid Deficiency / metabolism
  • Ascorbic Acid Deficiency / pathology
  • Azacitidine / administration & dosage
  • Azacitidine / analogs & derivatives*
  • Cell Proliferation / drug effects
  • DNA Methylation / drug effects
  • DNA-Binding Proteins / genetics
  • Decitabine
  • Drug Synergism
  • Endogenous Retroviruses / genetics
  • Enzyme Inhibitors / administration & dosage*
  • Female
  • Hematologic Neoplasms / complications
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / pathology
  • Humans
  • Interferons / genetics
  • Male
  • Methyltransferases / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • RNA, Double-Stranded / drug effects

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Double-Stranded
  • TET2 protein, human
  • Decitabine
  • Interferons
  • Methyltransferases
  • Azacitidine
  • Ascorbic Acid