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Título: | Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein Kinase C δ |
Autor: | García-Fernández, Luis F. CSIC; Losada, Alejandro CSIC; Alcaide, Victoria CSIC; Álvarez, Alberto; Cuadrado, Ana CSIC ORCID; González-Santiago, L. CSIC; Muñoz Terol, Alberto CSIC ORCID; Sánchez-Puelles, José María CSIC ORCID | Fecha de publicación: | 2002 | Editor: | Nature Publishing Group | Citación: | Oncogene 21(49): 7533-7544 (2002) | Resumen: | AplidinTM, a new antitumoural drug presently in phase II clinical trials, has shown both in vitro and in vivo activity against human cancer cells. AplidinTM effectively inhibits cell viability by triggering a canonical apoptotic program resulting in alterations in cell morphology, caspase activation, and chromatin fragmentation. Pro-apoptotic concentrations of AplidinTM induce early oxidative stress, which results in a rapid and persistent activation of both JNK and p38 MAPK and a biphasic activation of ERK. Inhibition of JNK and p38 MAPK blocks the apoptotic program induced by AplidinTM, demonstrating its central role in the integration of the cellular stress induced by the drug. JNK and p38 MAPK activation results in downstream cytochrome c release and activation of caspases -9 and -3 and PARP cleavage, demonstrating the mediation of the mitochondrial apoptotic pathway in this process. We also demonstrate that protein kinase C δ (PKC-) mediates the cytotoxic effect of AplidinTM and that it is concomitantly processed and activated late in the apoptotic process by a caspase mediated mechanism. Remarkably, cells deficient in PKC-δ show enhanced survival upon drug treatment as compared to its wild type counterpart. PKC-δ thus appears as an important component necessary for full caspase cascade activation and execution of apoptosis, which most probably initiates a positive feedback loop further amplifying the apoptotic process. | URI: | http://hdl.handle.net/10261/80089 | DOI: | 10.1038/sj.onc.1205972 | Identificadores: | doi: 10.1038/sj.onc.1205972 issn: 0950-9232 e-issn: 1476-5594 |
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