Rethinking the Combination of Proton Exchanger Inhibitors in Cancer Therapy

Abstract

Microenvironmental acidity is becoming a key target for the new age of cancer treatment. In fact, while cancer is characterized by genetic heterogeneity, extracellular acidity is a common phenotype of almost all cancers. To survive and proliferate under acidic conditions, tumor cells up-regulate proton exchangers and transporters (mainly V-ATPase, Na⁺/H⁺ exchanger (NHE), monocarboxylate transporters (MCTs), and carbonic anhydrases (CAs)), that actively extrude excess protons, avoiding intracellular accumulation of toxic molecules, thus becoming a sort of survival option with many similarities compared with unicellular microorganisms. These systems are also involved in the unresponsiveness or resistance to chemotherapy, leading to the protection of cancer cells from the vast majority of drugs, that when protonated in the acidic tumor microenvironment, do not enter into cancer cells. Indeed, as usually occurs in the progression versus malignancy, resistant tumor clones emerge and proliferate, following a transient initial response to a therapy, thus giving rise to more malignant behavior and rapid tumor progression. Recent studies are supporting the use of a cocktail of proton exchanger inhibitors as a new strategy against cancer.

Keywords: V-ATPases; acidity; carbonic anhydrase inhibitors; carbonic anhydrases; hypoxia; pH; proton pump inhibitors.

Figure 1

Proton flux regulators and their role in cancer. The aberrant expression and activity of proton exchangers leads to acidification of the tumor microenvironment and creates a reversed pH gradient across the plasma membrane leading to extracellular acidity and an alkaline, organelle-free cytosol.

Figure 2

Proton pump inhibitors (PPIs) mechanism of action. PPIs are weak base pro-drugs, that once in the acidic extracellular environment surrounding tumors, can be protonated, thereby reducing their ability to cross the membrane of cells. PPIs then bind irreversibly to proton pumps, dramatically inhibiting their activity, leading to inhibition of proton translocation across the plasma membrane, which in turn, induces alkalization of the tumor microenvironment.