Tris-base Buffer: A Promising New Inhibitor for Cancer Progression and Metastasis

Cancer Med. 2017 Jul;6(7):1720-1729. doi: 10.1002/cam4.1032. Epub 2017 May 29.

Abstract

Neutralizing tumor external acidity with oral buffers has proven effective for the prevention and inhibition of metastasis in several cancer mouse models. Solid tumors are highly acidic as a result of high glycolysis combined with an inadequate blood supply. Our prior work has shown that sodium bicarbonate, imidazole, and free-base (but not protonated) lysine are effective in reducing tumor progression and metastasis. However, a concern in translating these results to clinic has been the presence of counter ions and their potential undesirable side effects (e.g., hypernatremia). In this work, we investigate tris(hydroxymethyl)aminomethane, (THAM or Tris), a primary amine with no counter ion, for its effects on metastasis and progression in prostate and pancreatic cancer in vivo models using MRI and bioluminescence imaging. At an ad lib concentration of 200 mmol/L, Tris effectively inhibited metastasis in both models and furthermore led to a decrease in the expression of the major glucose transporter, GLUT-1. Our results also showed that Tris-base buffer (pH 8.4) had no overt toxicity to C3H mice even at higher doses (400 mmol/L). In conclusion, we have developed a novel therapeutic approach to manipulate tumor extracellular pH (pHe) that could be readily adapted to a clinical trial.

Keywords: Acidosis; GLUT-1; Tris-base; buffer therapy; metastasis; pancreatic cancer; prostate cancer.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Blood Chemical Analysis
  • Buffers*
  • Cell Line, Tumor
  • Cells, Cultured
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Hydrogen-Ion Concentration
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Inbred C3H
  • Molecular Imaging
  • Neoplasm Metastasis
  • Survival Analysis
  • Tromethamine / chemistry
  • Tromethamine / pharmacology*
  • Tumor Burden / drug effects
  • Urinalysis
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Buffers
  • Tromethamine