2026-07-13T00:07:16Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/48752022-10-03T09:46:44Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925

Manuel Manresa, Pilar . Korrodi Gregório, Luís Hernando Santa Cruz, Elsa Villanueva, Alberto . Martínez García, David Rodilla, Ananda M. Ramos, Ricard . Fardilha, Margarida . Moya, Juan . Quesada Pato, Roberto Soto Cerrato, Vanessa Pérez Tomás, Ricardo 2018-08-22T08:28:41Z 2018-08-22T08:28:41Z 2017-07 1535-7163 http://hdl.handle.net/10259/4875 10.1158/1535-7163.MCT-16-0752 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 of BCL2 and BIRC5/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. Spanish Government and EU funds through the Fondo de Investigaciones Sanitarias (FIS, project PI13/ 00089) and from La Marat o de TV3 Foundation (project 20132730) to R. P erez-Tom as. R. Ramos was supported by the Sociedad Espa~nola de Neumología y Cirugía Tor acica (SEPAR, Project 017/2013), R. Quesada by the Consejería de Educación de la Junta de Castilla y León (project BU340U13) and by the La Marat o de TV3 Foundation (project 20132732) and A. Villanueva by the FIS (project PI13/01339). application/pdf eng American Association for Cancer Research Molecular Cancer Therapeutics, 2017, V. 16, n. 7, p. 1224-1235 https://doi.org/10.1158/1535-7163.MCT-16-0752 info:eu-repo/grantAgreement/MSCBS/PI13-00089 info:eu-repo/grantAgreement/TV3Foundation/20132730 info:eu-repo/grantAgreement/SEPAR/017-2013 info:eu-repo/grantAgreement/JCyL/BU340U13 info:eu-repo/grantAgreement/TV3Foundation/20132732 info:eu-repo/grantAgreement/MSCBS/PI13-01339 Química orgánica Chemistry, Organic Novel indole-based tambjamine-analogues induce apoptotic lung cancer cell death through p38 mitogen-activated protein kinase activation info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion info:eu-repo/semantics/openAccess