Intraorganellar Acidification by V-ATPases: A Target in Cell Proliferation and Cancer Therapy

Abstract

Vacuolar-type ATPases are multicomponent proton pumps involved in the acidification of single membrane intracellular compartments such as endosomes and lysosomes. They couple the hydrolysis of ATP to the translocation of one to two protons across the membrane. Acidification of the lumen of single membrane organelles is a necessary factor for the correct traffic of membranes and cargo to and from the different internal compartments of a cell. Also, V-ATPases are involved in regulation of pH at the cytosol and, possibly, extracellular milieu. The inhibition of V-ATPases has been shown to induce apoptosis and cell cycle arrest in tumour cells and, therefore, chemicals that behave as inhibitors of this kind of proton pumps have been proposed as putative treatment agents against cancer and many have been patented as such. The compounds filed in patents fall into five major types: plecomacrolides, benzolactone enamides, archazolids, chondropsins and indoles. All these have proved to be apoptosis inducers in cell culture and many to be able to reduce xenograft tumor growth in murine models. The present review will summarize their general structure, origin and mechanisms of action and put them in relation to the patents registered so far for the treatment of cancer.

Intracellular Proton Pumps as Targets in Chemotherapy: V-ATPases and Cancer

“…Compounds active against V-ATPases raise a great interest, as judged by the number of preclinical tests published and the fair amount of patents issued [171]. However, V-ATPase inhibitors still face a tremendous challenge to be successful: their high toxicity.…”

A monoclonal antibody (Mc178-Ab) targeted to the ecto-ATP synthase β-subunit-induced cell apoptosis via a mechanism involving the MAKase and Akt pathways

“…Because intracellular acidification is able to induce cell apoptosis [31][32][33], disturbing the pH regulation of ATP synthase may be one of the mechanisms. It is known that acidity and hypoxia are typical characteristics of the tumor microenvironment and that cells are able to regulate themselves for survival under acidic conditions.…”

“…As a result, the intracellular pH began to decline until it achieved a balance. It has been demonstrated that low intracellular pH level play a passive role in cell proliferation [31,34]. Moreover, intracellular acidification is able to induce cell apoptosis by activating p38 MAPK or by inhibiting the phosphorylation of the Fig.…”

An Inhibitor of Na+/H+Exchanger (NHE), Ethyl-Isopropyl Amiloride (EIPA), Diminishes Proliferation of MKN28 Human Gastric Cancer Cells by Decreasing the Cytosolic Cl-Concentration via DIDS-Sensitive Pathways

“…However, if pH c of tumor cells is lowered by production of a large amount of H + , tumor cells would induce cell cycle arrest and apoptosis [5,6]. Therefore [7][8][9]. On the other hand, acidic microenvironments surrounding tumor cells produced by activation of H + transporters provide tumor cells with advantages for migration and invasion.…”