V-ATPase Inhibitors in Cancer Therapy: Targeting Intraorganellar Acidification

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 or 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. V-ATPases are also involved in the regulation of pH at the cytosol and, possibly, extracellular milieu. The inhibition of V-ATPases has been shown to induce apoptosis as well as cell cycle arrest in tumor cells; 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 are able to reduce xenograft tumor growth in murine models. The present chapter 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.

Keywords: Acidification, apicularen, apoptosis, archazolid, bafilomycin, cell cycle arrest, cell death, chondropsin, concanamycin, endosome, hidrazide, indole, lobatamide, lysosome, macrolide, organelle, palmerolide, salicylihalamide, VATPase, Warburg-effect.