2026-04-28T04:13:40Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/95732024-09-28T00:05:22Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925

Arias Betancur, Alain 38bb623a-30d8-4c4a-b321-e3d4e5365ce6 600 Fontova Pale, Pere 766 600 0000-0002-1352-3084 Alonso Carrillo, Daniel 761 600 0000-0002-6132-8953 Carreira Barral, Israel 763 600 0000-0002-4835-8752 Duis, Janneke eaa69e85-3e11-40b5-84b0-7cf28128e880 García Valverde, María 222 600 0000-0002-3990-8388 Soto Cerrato, Vanessa 346bb3c7-0c69-4d62-9045-26b0b8d37a51 600 Quesada Pato, Roberto 458 600 0000-0003-2764-7157 Pérez Tomás, Ricardo 3306d7a2-706a-47ab-8490-869a1b191c58 600 2024-09-27T10:02:40Z 2024-09-27T10:02:40Z 2024-11 0006-2952 http://hdl.handle.net/10259/9573 10.1016/j.bcp.2024.116469 Due to the relevance of lactic acidosis in cancer, several therapeutic strategies have been developed targeting its production and/or regulation. In this matter, inhibition approaches of key proteins such as lactate dehydrogenase or monocarboxylate transporters have showed promising results, however, metabolic plasticity and tumor heterogeneity limits their efficacy. In this study, we explored the anticancer potential of a new strategy based on disturbing lactate permeability independently of monocarboxylate transporters activity using a small molecule ionophore named Lactrans-1. Derived from click-tambjamines, Lactrans-1 facilitates transmembrane lactate transportation in liposome models and reduces cancer cell viability. The results showed that Lactrans-1 triggered both apoptosis and necrosis depending on the cell line tested, displaying a synergistic effect in combination with first-line standard chemotherapeutic cisplatin. The ability of this compound to transport outward lactate anions was confirmed in A549 and HeLa cells, two cancer cell lines having distinct rates of lactate production. In addition, through cell viability reversion experiments it was possible to establish a correlation between the amount of lactate transported and the cytotoxic effect exhibited. The movement of lactate anions was accompanied with intracellular pH disturbances that included basification of lysosomes and acidification of the cytosol and mitochondria. We also observed mitochondrial swelling, increased ROS production and activation of oxidative stress signaling pathways p38-MAPK and JNK/SAPK. Our findings provide evidence that enhancement of lactate permeability is critical for cellular pH homeostasis and effective to trigger cancer cell death, suggesting that Lactrans-1 may be a promising anticancer therapy. This work was supported by Consejería de Educación de la Junta de Castilla y León [Project BU067P20] and Ministerio de Ciencia e Innovación [Project PID2020-117610RB-100]. A.A.-B. thanks to PFCHA/Becas Chile (Folio #72200156) for his pre-doctoral scholarship. P.F., D.A.-C. and I.C.-B. thank Consejería de Educación de la Junta de Castilla y León, European Regional Development Fund (ERDF) and European Social Fund (ESF) for their post-doctoral (P.F. and I.C.-B.) and pre-doctoral (D.A.-C.) contracts. application/pdf eng Elsevier Biochemical Pharmacology. 2024, V. 229, 116469 https://doi.org/10.1016/j.bcp.2024.116469 info:eu-repo/grantAgreement/Junta de Castilla y León//BU067P20//Molecular tools targeting cellular metabolism for cancer therapy/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica, Técnica y de Innovación 2017-2020/PID2020-117610RB-I00/ES/SMALL MOLECULE TRANSMEMBRANE ANION CARRIERS FOR BIOLOGICAL APPLICATIONS/ info:eu-repo/grantAgreement/CONICYT/PFCHA/Folio #72200156/CL/ Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Lactate Anionophores Click-tambjamines Cancer metabolism pH deregulation Small molecules Bioquímica Química orgánica Biochemistry Chemistry, Organic Deregulation of lactate permeability using a small-molecule transporter (Lactrans-1) disturbs intracellular pH and triggers cancer cell death info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Biochemical Pharmacology 229 116469 THUMBNAIL Arias-bp_2024.pdf.jpg Arias-bp_2024.pdf.jpg IM Thumbnail image/jpeg 4960 https://riubu.ubu.es/bitstream/10259/9573/4/Arias-bp_2024.pdf.jpg 07800cc976abb111d0e86fdc5cbada04 MD5 4 LICENSE license.txt license.txt text/plain; charset=utf-8 999 https://riubu.ubu.es/bitstream/10259/9573/3/license.txt b295bcbce42e2caabeb0c623d3860c06 MD5 3 CC-LICENSE license_rdf license_rdf application/rdf+xml; charset=utf-8 908 https://riubu.ubu.es/bitstream/10259/9573/2/license_rdf 0175ea4a2d4caec4bbcc37e300941108 MD5 2 ORIGINAL Arias-bp_2024.pdf Arias-bp_2024.pdf application/pdf 8580037 https://riubu.ubu.es/bitstream/10259/9573/1/Arias-bp_2024.pdf 0ccc7a63f000920e4c972903817cf2f4 MD5 1 10259/9573 oai:riubu.ubu.es:10259/9573 2024-09-28 02:05:22.396 Repositorio Institucional de la Universidad de Burgos bubrep@ubu.es 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