Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

Luis F. García-Fernández, Alejandro Losada, Victoria Alcaide, Alberto M. Álvarez, Ana Cuadrado, Laura González, Keiko Nakayama, Keiichi I. Nakayama, José María Fernández-Sousa, Alberto Muñoz, José María Sánchez-Puelles

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115 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7533-7544
Number of pages12
JournalOncogene
Volume21
Issue number49
DOIs
Publication statusPublished - 2002 Jan 1
Externally publishedYes

Keywords

  • Aplidin™
  • Caspases
  • JNK
  • Oxidative damage
  • PKC-delta
  • p38

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    García-Fernández, L. F., Losada, A., Alcaide, V., Álvarez, A. M., Cuadrado, A., González, L., Nakayama, K., Nakayama, K. I., Fernández-Sousa, J. M., Muñoz, A., & Sánchez-Puelles, J. M. (2002). Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ. Oncogene, 21(49), 7533-7544. https://doi.org/10.1038/sj.onc.1205972