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Título : Novel indole-based tambjamine-analogues induce apoptotic lung cancer cell death through p38 mitogen-activated protein kinase activation
Autor : 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 .
Publicado en: Molecular Cancer Therapeutics, 2017, V. 16, n. 7, p. 1224-1235
Editorial : American Association for Cancer Research
Fecha de publicación : jul-2017
ISSN : 1535-7163
DOI: 10.1158/1535-7163.MCT-16-0752
Resumen : 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.
Materia: Química orgánica
Chemistry, Organic
URI : http://hdl.handle.net/10259/4875
Versión del editor: https://doi.org/10.1158/1535-7163.MCT-16-0752
Aparece en las colecciones: Artículos BIOORG

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