title: Novel Indole-based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through p38 Mitogen-Activated Protein Kinase Activation.
abstract: Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation ofBCL2andBIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer.Mol Cancer Ther; 16(7); 1224-35. ©2017 AACR.
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Manuel-Manresa
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.
authors.forename: Luís
authors.initials: L
authors.lastname: Korrodi-Gregório
authors.affiliation: Department of Chemistry, University of Burgos, Burgos, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Hernando
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institut of Oncology ICO, Bellvitge Biomedical Research Institute IDIBELL, L'Hospitalet, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Martínez-García
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: Ananda M
authors.initials: AM
authors.lastname: Rodilla
authors.affiliation: Department of Thoracic Surgery and University of Barcelona, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Ramos
authors.affiliation: Laboratory of Signal Transduction, Department of Medical Sciences, Institute for Research in Biomedicine-iBiMED, Health Sciences Program, University of Aveiro, Aveiro, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Fardilha
authors.affiliation: Department of Thoracic Surgery and University of Barcelona, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Moya
authors.affiliation: Department of Chemistry, University of Burgos, Burgos, Spain.
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. rperez@ub.edu vsoto@ub.edu.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Soto-Cerrato
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain. rperez@ub.edu vsoto@ub.edu.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pérez-Tomás
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage*; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
chemical_list: C107489:BIRC5 protein, human; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D000077022:Survivin; C551403:tambjamine K; D048051:p38 Mitogen-Activated Protein Kinases