Systemic deuteration of SCID mice using the water-isotopologue deuterium oxide (D2 O) inhibits tumor growth in an orthotopic bioluminescent model of human pancreatic ductal adenocarcinoma.

Abstract

Since its initial discovery as a natural isotopologue of dihydrogen oxide (1 H2 O), extensive research has focused on the biophysical, biochemical, and pharmacological effects of deuterated water (2 H2 O [D2 O, also referred to as "heavy water"]). Using a panel of cultured human pancreatic ductal adenocarcinoma (PDAC) cells we have profiled (i) D2 O-induced phenotypic antiproliferative and apoptogenic effects, (ii) redox- and proteotoxicity-directed stress response gene expression, and (iii) phosphoprotein-signaling related to endoplasmic reticulum (ER) and MAP-kinase stress response pathways. Differential array analysis revealed early modulation of stress response gene expression in both BxPC-3 and PANC-1 PDAC cells elicited by D2 O (90%; ≤6 h; upregulated: HMOX1, NOS2, CYP2E1, CRYAB, DDIT3, NFKBIA, PTGS1, SOD2, PTGS2; downregulated: RUNX1, MYC, HSPA8, HSPA1A) confirmed by independent RT-qPCR analysis. Immunoblot-analysis revealed rapid (≤6 h) onset of D2 O-induced MAP-kinase signaling (p-JNK, p-p38) together with ER stress response upregulation (p-eIF2α, ATF4, XBP1s, DDIT3/CHOP). Next, we tested the chemotherapeutic efficacy of D2 O-based drinking water supplementation in an orthotopic PDAC model employing firefly luciferase-expressing BxPC-3-FLuc cells in SCID mice. First, feasibility and time course of systemic deuteration (30% D2 O in drinking water; 21 days) were established using time-resolved whole-body proton magnetic resonance imaging and isotope-ratio mass spectrometry-based plasma (D/H)-analysis. D2 O-supplementation suppressed tumor growth by almost 80% with downregulated expression of PCNA, MYC, RUNX1, and HSP70 while increasing tumor levels of DDIT3/CHOP, HO-1, and p-eIF2α. Taken together, these data demonstrate for the first time that pharmacological induction of systemic deuteration significantly reduces orthotopic tumor burden in a murine PDAC xenograft model.

• Authors: Jana Jandova, Jean-Philippe Galons, David L Dettman, Georg T Wondrak
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 62 Issue 5 Pg. 598-612 (05 2023) ISSN: 1098-2744 [Electronic] United States
• PMID: 36727657 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Deuterium Oxide
• Drinking Water

Topics

• Humans
• Animals
• Mice
• Core Binding Factor Alpha 2 Subunit (pharmacology, therapeutic use)
• Mice, SCID
• Deuterium Oxide (pharmacology, therapeutic use)
• Drinking Water
• Cell Line, Tumor
• Pancreatic Neoplasms (genetics)
• Carcinoma, Pancreatic Ductal (genetics)
• Cell Proliferation
• Apoptosis