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 Nakayama, José María Fernández-Sousa, Alberto Muñoz, José María Sánchez-Puelles

Research output: Contribution to journalArticle

112 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 - Jan 1 2002

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p38 Mitogen-Activated Protein Kinases
Protein Kinase C
Protein Kinase C-delta
Oxidative Stress
Caspases
Pharmaceutical Preparations
Phase II Clinical Trials
Caspase 9
Cytochromes c
Human Activities
Caspase 3
Chromatin
Cell Survival
aplidine
Apoptosis
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

García-Fernández, L. F., Losada, A., Alcaide, V., Álvarez, A. M., Cuadrado, A., González, L., ... 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

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ. / García-Fernández, Luis F.; Losada, Alejandro; Alcaide, Victoria; Álvarez, Alberto M.; Cuadrado, Ana; González, Laura; Nakayama, Keiko; Nakayama, Keiichi; Fernández-Sousa, José María; Muñoz, Alberto; Sánchez-Puelles, José María.

In: Oncogene, Vol. 21, No. 49, 01.01.2002, p. 7533-7544.

Research output: Contribution to journalArticle

García-Fernández, LF, Losada, A, Alcaide, V, Álvarez, AM, Cuadrado, A, González, L, Nakayama, K, Nakayama, K, Fernández-Sousa, JM, Muñoz, A & Sánchez-Puelles, JM 2002, 'Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ', Oncogene, vol. 21, no. 49, pp. 7533-7544. https://doi.org/10.1038/sj.onc.1205972
García-Fernández LF, Losada A, Alcaide V, Álvarez AM, Cuadrado A, González L et al. Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ. Oncogene. 2002 Jan 1;21(49):7533-7544. https://doi.org/10.1038/sj.onc.1205972
García-Fernández, Luis F. ; Losada, Alejandro ; Alcaide, Victoria ; Álvarez, Alberto M. ; Cuadrado, Ana ; González, Laura ; Nakayama, Keiko ; Nakayama, Keiichi ; Fernández-Sousa, José María ; Muñoz, Alberto ; Sánchez-Puelles, José María. / Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ. In: Oncogene. 2002 ; Vol. 21, No. 49. pp. 7533-7544.
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