Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic...

Area of Science:

• Epigenetics
• Cancer Biology
• Nutritional Biochemistry

Background:

• Vitamin C (ascorbate) influences cancer-related gene expression through DNA demethylation via ten-eleven translocation (TET) enzymes.
• DNA methyltransferase (DNMT) enzymes counteract TET activity by increasing DNA methylation and suppressing gene expression.
• Dual oxidase (DUOX) enzymes, crucial for hydrogen peroxide production, are silenced in pancreatic ductal adenocarcinoma (PDAC).

Purpose of the Study:

• To investigate the synergistic effect of pharmacologic ascorbate (P-AscH-) and DNMT inhibitors on DUOX expression in PDAC.
• To evaluate the impact of this combination therapy on intracellular oxidation and cytotoxicity in PDAC models.

Main Methods:

• PDAC cells were treated with DNMT inhibitors to assess DUOX mRNA and protein expression.
• Combination therapy using P-AscH- and DNMT inhibitors was administered to PDAC cells in vitro and in vivo.
• Measurements included DUOX expression, intracellular oxidation levels, and cell viability.

Main Results:

• DNMT inhibitors alone induced a dose-dependent increase in DUOX expression in PDAC cells.
• The combination of P-AscH- and DNMT inhibitors significantly enhanced DUOX expression compared to single treatments.
• Combined therapy resulted in elevated intracellular oxidation and increased cytotoxicity in both in vitro and in vivo PDAC models.

Conclusions:

• Inhibiting DNMT synergizes with pharmacologic ascorbate to upregulate DUOX expression in pancreatic cancer.
• This epigenetic approach increases oxidative stress and enhances the anti-cancer effects of vitamin C in PDAC.
• The combination of P-AscH- and DNMT inhibition presents a promising therapeutic strategy for pancreatic cancer treatment.