RT info:eu-repo/semantics/article
T1 Novel indole-based tambjamine-analogues induce apoptotic lung cancer cell death through p38 mitogen-activated protein kinase activation
A1 Manuel Manresa, Pilar .
A1 Korrodi Gregório, Luís
A1 Hernando Santa Cruz, Elsa
A1 Villanueva, Alberto .
A1 Martínez García, David
A1 Rodilla, Ananda M.
A1 Ramos, Ricard .
A1 Fardilha, Margarida .
A1 Moya, Juan .
A1 Quesada Pato, Roberto
A1 Soto Cerrato, Vanessa
A1 Pérez Tomás, Ricardo
K1 Química orgánica
K1 Chemistry, Organic
AB 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.
PB American Association for Cancer Research
SN 1535-7163
YR 2017
FD 2017-07
LK http://hdl.handle.net/10259/4875
UL http://hdl.handle.net/10259/4875
LA eng
NO Spanish Government and EUfunds 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 Neumologíay Cirugía Tor acica (SEPAR, Project 017/2013), R. Quesada by the Consejeríade Educación de la Junta de Castilla y León (project BU340U13) and bythe La Marat o de TV3 Foundation (project 20132732) and A. Villanueva by theFIS (project PI13/01339).
DS Repositorio Institucional de la Universidad de Burgos
RD 04-dic-2024