Procaine and procainamide inhibit the Wnt canonical pathway by promoter demethylation of WIF-1 in lung cancer cells

Abstract

Abstract. Secreted Wingless type (Wnt) ligands have previously been shown to be involved in tumor developmental processes and oncogenesis. Aberrant promoter methylation of Wnt inhibitory factor-1 (WIF-1) is a fundamental mechanism of epigenetic silencing in human cancers. Procaine, a local anesthetic drug, and procainamide, a drug for the treatment of cardiac arrhythmias, have been reported as inhibitors of DNA methylation, causing demethylation and reactivation of methylation-silenced genes such as RARß and GSTP1. The promoter demethylation of WIF-1 has not previously been reported on. We demonstrated previously that WIF-1 is silenced due to promoter hypermethylation in lung cancer cell lines. In this study, we demonstrate promoter demethylation of WIF-1; restoration of WIF-1 expression, and underexpression of cytosolic ß-catenin protein and TCF reporter activity, after procaine and procainamide treatment in H460 and A549 cell lines. Our results provide the first evidence that procaine and procainamide reactivate WIF-1 in these cancer cells and downregulate the Wnt canonical pathway. These results further suggest that procaine and procainamide may have a potential use for preventing the development of lung cancer.

Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration

“…As shown in Figure 7, pretreatment with procaine (2 µM) per se did not modify the MC3T3-E1 cell ability to cover the wound, but completely prevented the positive action of δ-TT on MC3T3-E1 cell migration. The involvement of β-catenin in the enhancing action of δ-TT on MC3T3-E1 cell migration was confirmed by the results obtained with procaine, an inhibitor of the Wnt/β-catenin signalling pathway [20,21]. As shown in Figure 7, pretreatment with procaine (2 μM) per se did not modify the MC3T3-E1 cell ability to cover the wound, but completely prevented the positive action of δ-TT on MC3T3-E1 cell migration.…”

“…Even if the lack of measurements of the intranuclear translocation of β-catenin represents a limitation of our study, we suggest that the canonical Wnt signalling pathway is involved in the effect of δ-TT on MC3T3-E1 cell migration since δ-TT treatment increased β-catenin transcriptional activity as detected by luciferase assay and pretreatment with procaine, a local anaesthetic drug, previously reported to inhibit the Wnt/β-catenin pathway [20,21], prevents the increase of the wound healing activity induced by δ-TT. Our assumption is in line with previous in vivo studies, showing that oral annatto TT supplementation prevented osteopenia induced by metabolic syndrome by reducing SOST and DKK1 levels, considered antagonist of the Wnt signalling pathway [33].…”

Reply: “Comment on: Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration. Int. J. Mol. Sci. 2020, 21, 4661”

“…Pretreatment with procaine, a local anesthetic drug, previously reported to inhibit the Wnt/β-catenin pathway [14,15], prevented the stimulatory action of δ-TT on cell migration.…”

Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Cancer Treatment?

“…In breast cancer cell lines, procaine induces DNA demethylation in CpG islands, triggering a 40% reduction in 5-methyl-cytosine (5mC) content and the re-expression of epigenetically-silenced genes [39]. In other tumor models, particularly gastric cancer, hepatocellular carcinoma (HCC) and nonsmall cell lung cancer (NSCLC), procaine also demonstrated nonepigenetic effects such as cell proliferation inhibition, apoptosis enhancement [41], cell cycle arrest [40] and downregulation of Wnt signaling pathway activation [37]. The FDA-approved drug procainamide is a derivative of procaine, used in the treatment of cardiac arrythmia.…”