{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:25:21Z","timestamp":1770971121103,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T00:00:00Z","timestamp":1612828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/103025\/2014"],"award-info":[{"award-number":["SFRH\/BD\/103025\/2014"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-007038"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007038"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006742","name":"Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio","doi-asserted-by":"publisher","award":["MetabRes_CESPU_2017"],"award-info":[{"award-number":["MetabRes_CESPU_2017"]}],"id":[{"id":"10.13039\/501100006742","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The reverse pH gradient is a major feature associated with cancer cell reprogrammed metabolism. This phenotype is supported by increased activity of pH regulators like ATPases, carbonic anhydrases (CAs), monocarboxylate transporters (MCTs) and sodium\u2013proton exchangers (NHEs) that induce an acidic tumor microenvironment, responsible for the cancer acid-resistant phenotype. In this work, we analyzed the expression of these pH regulators and explored their inhibition in breast cancer cells as a strategy to enhance the sensitivity to chemotherapy. Expression of the different pH regulators was evaluated by immunofluorescence and Western blot in two breast cancer cell lines (MDA-MB-231 and MCF-7) and by immunohistochemistry in human breast cancer tissues. Cell viability, migration and invasion were evaluated upon exposure to the pH regulator inhibitors (PRIs) concanamycin-A, cariporide, acetazolamide and cyano-4-hydroxycinnamate. Additionally, PRIs were combined with doxorubicin to analyze the effect of cell pH dynamic disruption on doxorubicin sensitivity. Both cancer cell lines expressed all pH regulators, except for MCT1 and CAXII, only expressed in MCF-7 cells. There was higher plasma membrane expression of the pH regulators in human breast cancer tissues than in normal breast epithelium. Additionally, pH regulator expression was significantly associated with different molecular subtypes of breast cancer. pH regulator inhibition decreased cancer cell aggressiveness, with a higher effect in MDA-MB-231. A synergistic inhibitory effect was observed when PRIs were combined with doxorubicin in the breast cancer cell line viability. Our results support proton dynamic disruption as a breast cancer antitumor strategy and the use of PRIs to boost the activity of conventional therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics13020242","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T08:53:56Z","timestamp":1613292836000},"page":"242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Disruption of pH Dynamics Suppresses Proliferation and Potentiates Doxorubicin Cytotoxicity in Breast Cancer Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9367-5979","authenticated-orcid":false,"given":"Diana","family":"Tavares-Valente","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"},{"name":"PT Government Associate Laboratory, ICVS\/3B\u2019s\u2014Life and Health Sciences Research Institute\/Biomaterials, Biodegradables and Biomimetics, 4710-057 Braga\/Guimar\u00e3es, Portugal"},{"name":"Department of Sciences, IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-022X","authenticated-orcid":false,"given":"B\u00e1rbara","family":"Sousa","sequence":"additional","affiliation":[{"name":"IPATIMUP\u2014Institute of Molecular Pathology and Immunology of the University of Porto, University of Porto, 4200-135 Porto, Portugal"},{"name":"i3S\u2014Institute for Research &amp; Innovation in Health, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1006-6946","authenticated-orcid":false,"given":"Fernando","family":"Schmitt","sequence":"additional","affiliation":[{"name":"IPATIMUP\u2014Institute of Molecular Pathology and Immunology of the University of Porto, University of Porto, 4200-135 Porto, Portugal"},{"name":"FMUP\u2014Faculty of Medicine of the University of Porto, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1770-4544","authenticated-orcid":false,"given":"F\u00e1tima","family":"Baltazar","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"},{"name":"PT Government Associate Laboratory, ICVS\/3B\u2019s\u2014Life and Health Sciences Research Institute\/Biomaterials, Biodegradables and Biomimetics, 4710-057 Braga\/Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5912-3409","authenticated-orcid":false,"given":"Od\u00edlia","family":"Queir\u00f3s","sequence":"additional","affiliation":[{"name":"Department of Sciences, IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,9]]},"reference":[{"key":"ref_1","unstructured":"International Agency for Research on Cancer (2020, December 03). 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