Intraorganellar acidification by V-ATPases: a target in cell proliferation and cancer therapy.
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.
Hernández
Agustín
A
Instituto de Bioquímica Vegetal y Fotosíntesis, CSIC-Universidad de Sevilla, Avda. Américo Vespucio 49, 41092 Seville, Spain. agustin.hernandez@ibvf.csic.es
Serrano
Gloria
G
Herrera-Palau
Rosana
R
Pérez-Castiñeira
José R
JR
Serrano
Aurelio
A
D000143:Acids / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D015388:Organelles / Q000378:metabolism*; D010330:Patents as Topic; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*
D000143:Acids; D000970:Antineoplastic Agents; D025262:Vacuolar Proton-Translocating ATPases