Utilize este identificador para referenciar este registo: https://hdl.handle.net/1822/72538

TítuloDisruption of pH dynamics suppresses proliferation and potentiates doxorubicin cytotoxicity in breast cancer cells
Autor(es)Tavares-Valente, Diana
Sousa, Bárbara
Schmitt, Fernando
Baltazar, Fátima
Queirós, Odília
Palavras-chavepH regulators
reverse pH gradient
tumor microenvironment
treatment resistance
Data2021
EditoraMultidisciplinary Digital Publishing Institute
RevistaPharmaceutics
CitaçãoTavares-Valente, D.; Sousa, B.; Schmitt, F.; Baltazar, F.; Queirós, O. Disruption of pH Dynamics Suppresses Proliferation and Potentiates Doxorubicin Cytotoxicity in Breast Cancer Cells. Pharmaceutics 2021, 13, 242. https://doi.org/10.3390/pharmaceutics13020242
Resumo(s)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–proton 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.
TipoArtigo
URIhttps://hdl.handle.net/1822/72538
DOI10.3390/pharmaceutics13020242
e-ISSN1999-4923
Versão da editorahttps://www.mdpi.com/1999-4923/13/2/242
AcessoAcesso aberto
Aparece nas coleções:ICVS - Artigos em revistas internacionais / Papers in international journals

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