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.
Highlights
The extracellular pH of tumors is acidic as compared to normal tissue
Despite the fact that decreased extracellular tumor pH is associated with numerous cellular H+ exporting mechanisms, such as Na–H exchangers, vacuolar ATPases, and carbonic anhydrases [1,2,3], glycolysis is considered the major cause of tumor acidity
We observed no significant differences in mouse weights between tap water and 200 mmol/L Tris–base up to 70 days, after that, mice weight started to drop on the 400 mmol/L-- treated mice compared to tap-and 200 mmol/L-treated mice (***P < 0.003) while the 400 mmol/L Tris-treated group had a slower weight gain in comparison, which may be due to a diuretic effect of Tris–base
Summary
The extracellular pH (pHe) of tumors is acidic as compared to normal tissue. Despite the fact that decreased extracellular tumor pH is associated with numerous cellular H+ exporting mechanisms, such as Na–H exchangers, vacuolar ATPases, and carbonic anhydrases [1,2,3], glycolysis is considered the major cause of tumor acidity. We have observed that this acidic pHe is important, and perhaps sufficient, for the transition from an in situ to an invasive cancer, and have proposed a microenvironmental model of carcinogenesis that is focused on the barriers to cellular proliferation at different stages of cancer evolution [6, 7]. We have investigated this model at the microscopic level using window chambers and computer models to show that tumor acidosis promotes invasion that is enhanced by poor perfusion [8, 9]. It has been shown that the tumor invasive edge is highly acidic, and encompasses cells that highly expressed the glucose transporter, GLUT-1 [9]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.