title: Proton channels and exchangers in cancer.
abstract: Although cancer is characterized by an intratumoral genetic heterogeneity, a totally deranged pH control is a common feature of most cancer histotypes. Major determinants of aberrant pH gradient in cancer are proton exchangers and transporters, including V-ATPase, Na+/H+ exchanger (NHE), monocarboxylate transporters (MCTs) and carbonic anhydrases (CAs). Thanks to the activity of these proton transporters and exchangers, cancer becomes isolated and/or protected not only from the body reaction against the growing tumor, but also from the vast majority of drugs that when protonated into the acidic tumor microenvironment do not enter into cancer cells. Proton transporters and exchangers represent a key feature tumor cells use to survive in the very hostile microenvironmental conditions that they create and maintain. Detoxifying mechanisms may thus represent both a key survival option and a selection outcome for cells that behave as unicellular microorganisms rather than belonging to an organ, compartment or body. It is, in fact, typical of malignant tumors that, after a clinically measurable yet transient initial response to a therapy, resistant tumor clones emerge and proliferate, thus bursting a more malignant behavior and rapid tumor progression. This review critically presents the background of a novel and efficient approach that aims to fight cancer through blocking or inhibiting well characterized proton exchangers and transporters active in human cancer cells. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
authors.affiliation: Anti-Cancer Drug Section, Department of Drug Research and Medicine Evaluation, Istituto Superiore di Sanità (National Institute of Health), Rome, Italy.
authors.forename: Enrico Pierluigi
authors.initials: EP
authors.lastname: Spugnini
authors.affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.affiliation: Department of Gastroenterology, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Stock
authors.affiliation: Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Dentistry, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Perez-Sayans
authors.affiliation: Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Angelo
authors.initials: A
authors.lastname: De Milito
authors.affiliation: Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.affiliation: Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Dentistry, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.
authors.forename: Abel Garcìa
authors.initials: AG
authors.lastname: Garcìa
authors.affiliation: Instituto de Biología Clínica y Metabolismo (IBCM), (Postas) Vitoria, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Harguindey
authors.affiliation: Anti-Cancer Drug Section, Department of Drug Research and Medicine Evaluation, Istituto Superiore di Sanità (National Institute of Health), Rome, Italy. Electronic address: stefano.fais@iss.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054328:Proton Pump Inhibitors / Q000627:therapeutic use*; D011522:Protons; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D027501:Monocarboxylic Acid Transporters; D054328:Proton Pump Inhibitors; D011522:Protons; D017923:Sodium-Hydrogen Exchangers; D025262:Vacuolar Proton-Translocating ATPases; D002256:Carbonic Anhydrases
keywords: Cancer; Carbonic anhydrases; Monocarboxylate transporters; Na(+)/H(+) exchanger; Proton exchangers; V-ATPase