{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T06:46:20Z","timestamp":1792478780123,"version":"4.5.0"},"reference-count":171,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2017,12,23]],"date-time":"2017-12-23T00:00:00Z","timestamp":1513987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/metabo8010002","type":"journal-article","created":{"date-parts":[[2017,12,26]],"date-time":"2017-12-26T03:06:38Z","timestamp":1514257598000},"page":"2","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Rethinking the Combination of Proton Exchanger Inhibitors in Cancer Therapy"],"prefix":"10.3390","volume":"8","author":[{"given":"Elisabetta","family":"Iessi","sequence":"first","affiliation":[{"name":"Department of Oncology and Molecular Medicine, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariantonia","family":"Logozzi","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Mizzoni","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Di Raimo","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu","family":"Supuran","sequence":"additional","affiliation":[{"name":"Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Laboratorio di Chimica Bioinorganica, Universit\u00e0 degli Studi di Firenze, Polo Scientifico, Via U. 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