Vacuolar-ATPase proton pump inhibition in cancer therapy: Veterinary and human experience

Cancer comprises a broad spectrum of diseases characterized by uncontrolled growth, different genetic mutations and a tendency to overcome the neighboring normal cells. The only common characteristic is the lack of pH control in the tumor milieu promoting an aberrant pH gradient. This phenomenon, unique to cancer cells, is promoted by a large family of proton exchangers and transporters, including V-ATPase, Na⁺/H⁺ exchanger (NHE), monocarboxylate transporters (MCTs) and carbonic anhydrases (CAs). This acid environment acts as a chemical shield that protects cancer cells from the immune response as well as most of the anticancer agents used by oncologists. The early transition from aerobic to anaerobic glucose metabolism is prompted and implemented through the over-expression of proton transporters. Among them, the vacuolar-ATPase proton system plays a pivotal role in this detoxifying network and their expression is often linked to the tumors' degree of malignancy. Vacuolar-ATPase proton pump inhibition has proven highly effective per se and capable of increasing the effectiveness of current chemotherapy protocols.