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      Rethinking the Combination of Proton Exchanger Inhibitors in Cancer Therapy

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          Abstract

          Microenvironmental acidity is becoming a key target for the new age of cancer treatment. In fact, while cancer is characterized by genetic heterogeneity, extracellular acidity is a common phenotype of almost all cancers. To survive and proliferate under acidic conditions, tumor cells up-regulate proton exchangers and transporters (mainly V-ATPase, Na +/H + exchanger (NHE), monocarboxylate transporters (MCTs), and carbonic anhydrases (CAs)), that actively extrude excess protons, avoiding intracellular accumulation of toxic molecules, thus becoming a sort of survival option with many similarities compared with unicellular microorganisms. These systems are also involved in the unresponsiveness or resistance to chemotherapy, leading to the protection of cancer cells from the vast majority of drugs, that when protonated in the acidic tumor microenvironment, do not enter into cancer cells. Indeed, as usually occurs in the progression versus malignancy, resistant tumor clones emerge and proliferate, following a transient initial response to a therapy, thus giving rise to more malignant behavior and rapid tumor progression. Recent studies are supporting the use of a cocktail of proton exchanger inhibitors as a new strategy against cancer.

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          Most cited references 155

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          On the origin of cancer cells.

           O WARBURG (1956)
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            Drug resistance and the solid tumor microenvironment.

            Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.
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              The vacuolar (H+)-ATPases--nature's most versatile proton pumps.

              The pH of intracellular compartments in eukaryotic cells is a carefully controlled parameter that affects many cellular processes, including intracellular membrane transport, prohormone processing and transport of neurotransmitters, as well as the entry of many viruses into cells. The transporters responsible for controlling this crucial parameter in many intracellular compartments are the vacuolar (H+)-ATPases (V-ATPases). Recent advances in our understanding of the structure and regulation of the V-ATPases, together with the mapping of human genetic defects to genes that encode V-ATPase subunits, have led to tremendous excitement in this field.
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                Author and article information

                Journal
                Metabolites
                Metabolites
                metabolites
                Metabolites
                MDPI
                2218-1989
                23 December 2017
                March 2018
                : 8
                : 1
                Affiliations
                [1 ]Department of Oncology and Molecular Medicine, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy; elisabetta.iessi@ 123456iss.it (E.I.); mariantonia.logozzi@ 123456iss.it (M.L.); davide.mizzoni@ 123456iss.it (D.M.); rosella.diraimo@ 123456iss.it (R.D.R.)
                [2 ]Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy; claudiu.supuran@ 123456unifi.it
                Author notes
                [* ]Correspondence: stefano.fais@ 123456iss.it ; Tel.: +39-06-4990-3195; Fax: +39-06-4990-2436
                Article
                metabolites-08-00002
                10.3390/metabo8010002
                5875992
                29295495
                7bce7fa3-b5ca-4751-9b76-eeec9c23c69b
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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