2026-04-28T08:54:59Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/43532022-04-29T12:02:46Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925

Rodilla, Ananda M. 5c2d53ae-ffde-4780-be5a-e5d395b46b91 500 Korrodi Gregório, Luís . 71ed3c06-9178-41c9-b2da-6cced4d016c2 500 Hernando Santa Cruz, Elsa 279 500 Manuel Manresa, Pilar . 0e8b3cef-7ea1-44a8-af01-7b49c8f0e385 500 Quesada Pato, Roberto 458 500 Pérez Tomás, Ricardo 3306d7a2-706a-47ab-8490-869a1b191c58 500 Soto Cerrato, Vanessa 346bb3c7-0c69-4d62-9045-26b0b8d37a51 500 2017-03-09T09:35:27Z 2018-02-01T03:45:06Z 2017-02 http://hdl.handle.net/10259/4353 Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with innovative mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favours cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing body of evidence supporting ionophores as novel antitumour drugs. Despite this, little is known about the implications of pH deregulation and homeostasis imbalance triggered by ionophores at the cellular level. In this work, we deeply analyse for the first time the anticancer effects of tambjamine analogues, a group of highly effective anion selective ionophores, at the cellular and molecular levels. First, their effects on cell viability were determined in several lung cancer cell lines and patient-derived cancer stem cells, demonstrating their potent cytotoxic effects. Then, we have characterized the induced lysosomal deacidification, as well as, the massive cytoplasmic vacuolization observed after treatment with these compounds, which is consistent with mitochondrial swelling. Finally, the activation of several proteins involved in stress response, autophagy and apoptosis was also detected, although they were not significantly responsible for the cell death induced. Altogether, these evidences suggest that tambjamine analogues provoke an imbalance in cellular ion homeostasis that triggers mitochondrial dysfunction and lysosomal deacidification leading to a potent cytotoxic effect through necrosis in lung cancer cell lines and cancer stem cells. Spanish government and the EU (FIS PI13/00089), Consejería de Educación de la Junta de Castilla y León (BU340U13 and BU092U16). application/pdf eng Elsevier Biochemical Pharmacology. 2017. V. 126, p. 23–33 http://dx.doi.org/10.1016/j.bcp.2016.11.022 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Anionophores Synthetictambjamine analogues Lysosomal dysfunction Autophagy blockade Necrosis Chemistry, Organic Química orgánica Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion CC-LICENSE license_rdf license_rdf application/rdf+xml; charset=utf-8 805 https://riubu.ubu.es/bitstream/10259/4353/8/license_rdf 4460e5956bc1d1639be9ae6146a50347 MD5 8 THUMBNAIL Rodilla-BP_2017.pdf.jpg Rodilla-BP_2017.pdf.jpg IM Thumbnail image/jpeg 4297 https://riubu.ubu.es/bitstream/10259/4353/7/Rodilla-BP_2017.pdf.jpg 4ca8cc5939a59b8c4983abaed29b8e54 MD5 7 ORIGINAL Rodilla-BP_2017.pdf Rodilla-BP_2017.pdf application/pdf 1083465 https://riubu.ubu.es/bitstream/10259/4353/1/Rodilla-BP_2017.pdf 488c25f0ae3bd0b9722ba3401b5f0529 MD5 1 LICENSE license.txt license.txt text/plain; charset=utf-8 1362 https://riubu.ubu.es/bitstream/10259/4353/5/license.txt 5d013bfa6e473ff0db22cd82a4d71a70 MD5 5 TEXT Rodilla-BP_2017.pdf.txt Rodilla-BP_2017.pdf.txt Extracted text text/plain 53011 https://riubu.ubu.es/bitstream/10259/4353/6/Rodilla-BP_2017.pdf.txt 2c2b2c408fc5e212c554042c82a2cafc MD5 6 10259/4353 oai:riubu.ubu.es:10259/4353 2022-04-29 14:02:46.255 Repositorio Institucional de la Universidad de Burgos bubrep@ubu.es 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