Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells

Cancer Res. 2003 Aug 15;63(16):4984-9.


Methylation-associated silencing of tumor suppressor genes is recognized as being a molecular hallmark of human cancer. Unlike genetic alterations, changes in DNA methylation are potentially reversible. This possibility has attracted considerable attention from a therapeutics standpoint. Nucleoside-analogue inhibitors of DNA methyltransferases, such as 5-aza-2'-deoxycytidine, are able to demethylate DNA and restore silenced gene expression. Unfortunately, the clinical utility of these compounds has not yet been fully realized, mainly because of their side effects. A few non-nucleoside inhibitors of DNA methyltransferases have been reported, including the anti-arrhythmia drug procainamide. Following this need to find new demethylating agents, we have tested the potential use of procaine, an anesthetic drug related to procainamide. Using the MCF-7 breast cancer cell line, we have found that procaine is a DNA-demethylating agent that produces a 40% reduction in 5-methylcytosine DNA content as determined by high-performance capillary electrophoresis or total DNA enzyme digestion. Procaine can also demethylate densely hypermethylated CpG islands, such as those located in the promoter region of the RAR beta 2 gene, restoring gene expression of epigenetically silenced genes. This property may be explained by our finding that procaine binds to CpG-enriched DNA. Finally, procaine also has growth-inhibitory effects in these cancer cells, causing mitotic arrest. Thus, procaine is a promising candidate agent for future cancer therapies based on epigenetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • CpG Islands
  • DNA / metabolism
  • DNA Methylation*
  • Dose-Response Relationship, Drug
  • Genes, Tumor Suppressor
  • Humans
  • Procaine / metabolism
  • Procaine / pharmacology*
  • Receptors, Retinoic Acid / genetics
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • Procaine
  • DNA