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Title: Novel indole-based tambjamine-analogues induce apoptotic lung cancer cell death through p38 mitogen-activated protein kinase activation
Author: Manuel-Manresa, Pilar
Korrodi-Gregório, Luís
Hernando, Elsa
Villanueva Garatachea, Alberto
Martínez García, David
Rodilla Martín, Ananda Marina
Ramos Izquierdo, Ricard
Fardilha, Margarida
Moya Amorós, Juan
Quesada, Roberto
Soto Cerrato, Vanessa
Pérez Tomás, Ricardo E.
Keywords: Apoptosi
Efectes secundaris dels medicaments
Càncer de pulmó
Drug side effects
Lung cancer
Issue Date: 1-Jul-2017
Publisher: American Association for Cancer Research
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 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. Mol Cancer Ther; 16(7); 1224-35. ©2017 AACR.
Note: Versió postprint del document publicat a:
It is part of: Molecular Cancer Therapeutics, 2017, vol. 16, num. 7, p. 1224-1235
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ISSN: 1535-7163
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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