Targeting the pH Paradigm at the Bedside: A Practical Approach

Abstract

The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the "cancer problem"? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article's goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.

Keywords: acetazolamide; amiloride; pH paradigm; pHtome; proton pump inhibitors; quercetin; repurposed drugs; topiramate.

Figure 1

Mechanisms of action of the pHtome participants.

Figure 2

Mechanism of pH threshold modification of NHE1.

Figure 3

Mechanism of action of NHE1 and VGSCs. NHE1 is an exchanger that imports sodium ions while exporting protons (hydrogen ions). This proton removal from the cell increases intracellular pH while it increases in the extracellular space. VGSCs import sodium ions but do not export protons. Among their other effects, the importance of VGSCs lies in the fact that they activate NHE1 [44]. Activating NHE1 means that it “starts working” at a higher intracellular pH. Under normal conditions, NHE1 has a pH_i threshold and becomes active when pH_i goes below it. VGSCs increase the threshold, leading to NHE activation even under higher intracellular pH. There is a well-established relationship among growth factors, NHE1, intracellular increase of pH, and proliferation [35,45,46,47,48,49]. NHEs mediate the signaling of growth factors and proton sensing [50,51,52] (Box 2).

Figure 4

Membrane carbonic anhydrase IX generates carbonic acid through hydration of CO₂. Carbon dioxide diffuses from inside the cell and is a product of cellular metabolism. Carbonic acid is immediately ionized to bicarbonate and a proton. While the proton remains in the extracellular space contributing to its acidity, the bicarbonate ion is imported into the cell by NBC1 contributing to increasing pH_i. CAIX (carbonic anhydrase 9) and CAXII (carbonic anhydrase 12) have been found to be potent drivers of cancer growth by alkalinizing the intracellular milieu [70].

Figure 5

V-ATPase proton pump mechanism of action.

Figure 6

Lactate extruder function of MCT4. Lactate originates from the enzymatic glycolysis of glucose introduced from the extracellular space with the mediation of glucose transporters (GLUTs). MCT4 is the main lactate exporter, while MCT1 imports lactate into the oxidative cells participating in the lactate shuttle.

Figure 7

The tandem work of NKCC1 and the Cl/CO3H exchanger alkalinize the intracellular milieu. Loop diuretics in general have the ability to inhibit NKCC1. The energy required for NKCC1 is provided by the electrochemical gradient of sodium [113,114,115,116,117]. The pH_i stabilizing properties of the chloride/bicarbonate exchanger have been clearly demonstrated in osteoclasts [118] and kidneys. In cancer, it works in close association with cytoplasmic carbonic anhydrase II [119], with a final result of proton extrusion [120]. While NKCC1 increases intracellular Cl⁻, this molecule is re-exported by the exchanger, allowing the import of bicarbonate. Bicarbonate transport in cancer is a pivotal issue in the pH paradigm [121]. Disulfiram, a drug used to treat alcoholism, has been shown to decrease the activity of the chloride/bicarbonate exchanger [122].

Figure 8

Year 2017: Front view: rib metastasis, iliac bone metastasis, increased radionuclide caption at maxillary alveolar level. Dorsal view: 4–5 dorsal vertebra metastasis. These images were similar to those of 2014. Absence of right kidney due to radical nephrectomy in 2003. Left panel anterior view. Second panel posterior view. Four right panels: upper left: posterior view, upper right: anterior view, lower left: right ribs, lower right: left ribs.

Figure 9

Year 2018: Front view: rib metastasis, iliac bone metastasis, increased radionuclide caption at maxillary alveolar level. Stable disease.