2026-06-20T03:25:21Zhttps://riubu.ubu.es/oai/request

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

00925njm 22002777a 4500 dc Arias Betancur, Alain author Fontova Pale, Pere author Alonso Carrillo, Daniel author Carreira Barral, Israel author Duis, Janneke author García Valverde, María author Soto Cerrato, Vanessa author Quesada Pato, Roberto author Pérez Tomás, Ricardo author 2024-11 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. 0006-2952 http://hdl.handle.net/10259/9573 10.1016/j.bcp.2024.116469 Lactate Anionophores Click-tambjamines Cancer metabolism pH deregulation Small molecules Deregulation of lactate permeability using a small-molecule transporter (Lactrans-1) disturbs intracellular pH and triggers cancer cell death