title: Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer.
abstract: 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.
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain. Electronic address: ananda.rodilla@ub.edu.
authors.forename: Ananda M
authors.initials: AM
authors.lastname: Rodilla
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Laboratory of Signal Transduction, Department of Medical Sciences, Institute for Research in Biomedicine - iBiMED, Health Sciences Program, University of Aveiro, Aveiro, Portugal. Electronic address: korrodi@ub.edu.
authors.forename: Luís
authors.initials: L
authors.lastname: Korrodi-Gregório
authors.affiliation: Department of Chemistry, University of Burgos, Burgos, Spain. Electronic address: ehsanta@ubu.es.
authors.forename: Elsa
authors.initials: E
authors.lastname: Hernando
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain. Electronic address: pilarmanuel@ub.edu.
authors.forename: Pilar
authors.initials: P
authors.lastname: Manuel-Manresa
authors.affiliation: Department of Chemistry, University of Burgos, Burgos, Spain. Electronic address: rquesada@ubu.es.
authors.forename: Roberto
authors.initials: R
authors.lastname: Quesada
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain. Electronic address: rperez@ub.edu.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pérez-Tomás
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain. Electronic address: vsoto@ub.edu.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Soto-Cerrato
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007476:Ionophores / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D053142:Mitochondrial Size; D009336:Necrosis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007476:Ionophores; D011758:Pyrroles
keywords: Anionophores; Autophagy blockade; Lysosomal dysfunction; Necrosis; Synthetic tambjamine analogues