Abstract
Aplidin™, a new antitumoural drug presently in phase II clinical trials, has shown both in vitro and in vivo activity against human cancer cells. Aplidin™ 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 Aplidin™ 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 Aplidin™, 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 delta (PKC-δ) mediates the cytotoxic effect of Aplidin™ 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.
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Acknowledgements
We would like to thank Juan M López-Oliva for excellent technical assistance and members of the R+D Department of PharmaMar, S.A. We also thank Drs Simon Munt and José Antonio López-Martín for critical reading of the manuscript and fruitful suggestions.
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García-Fernández, L., Losada, A., Alcaide, V. et al. Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ. Oncogene 21, 7533–7544 (2002). https://doi.org/10.1038/sj.onc.1205972
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DOI: https://doi.org/10.1038/sj.onc.1205972
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