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Critical role of the death receptor pathway in the antitumoral effects induced by hispanolone derivatives

Oncogene volume 32, pages 259–268 (2013)Cite this article

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Abstract

Labdane diterpenoids have a broad spectrum of biological activities including antibacterial, antiviral and anti-inflammatory properties. However, little is known about their possible role in the apoptotic cell death machinery. Here, we report that hispanolone derivatives, a group of labdane diterpenoids, induce apoptosis in different tumor cell lines by activating caspase-8 with subsequent participation of mitochondrial signaling. Activation of caspase-8 by hispanolone derivatives was followed by a decrease in mitochondrial membrane potential, the release of apoptotic factors from mitochondria to the cytosol, and activation of caspases-9 and 3. Hispanolone derivatives also led to a time-dependent cleavage of Bid. Inhibition of caspase-8 abrogated these processes, suggesting that the death receptor pathway has a critical role in the apoptotic events induced by hispanolone derivatives. In addition, silencing death receptors with small interfering RNA s or pretreating cells with neutralizing antibodies to Fas ligand, tumor necrosis factor receptor 1 (TNF-R1), and TNF-α receptor 2 (TRAIL) inhibited diterpenoid-induced apoptosis, revealing it to be dependent on these death receptors. Interestingly, hispanolone derivatives had no effect on non-tumor cells. Consistently, in vivo bioluminescence imaging corroborates this antineoplasic effect, as hispanolone derivatives significantly decrease cancer growth in tumor xenograft assays. These data demostrate the antitumoral effects of hispanolone derivatives and provide relevant preclinical validation for the use of these compounds as potent therapeutic agents in cancer treatment.

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Acknowledgements

This study was supported by grant PI08.0070 from the FIS and MPY 1410/09 from ISCIII to SH, and by a Santander-Complutense grant to SH and B de las H. We thank Gemma Benito for excellent technical assistance and Simon Bartlett for critical reading of the manuscript. We thank Dr S Alemany and Dr K Roby for kindly provide luc-B16F10 and ID8 cells, respectively.

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Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain

    P G Través & L Boscá

  2. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    R López-Fontal

  3. Departamento de Farmacología. Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid, Spain

    I Cuadrado & B de las Heras

  4. Oncohematología y Trasplante. FIB Hospital Universitario Niño Jesús and IIS Hospital La Princesa, Madrid, Spain

    A Luque

  5. Unidad de Inflamación y Cáncer, Área de Biología Celular y Desarrollo, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain

    S Hortelano

  6. These authors contributed equally to this work,

    P G Través & R López-Fontal

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  1. P G Través
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  2. R López-Fontal
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Corresponding authors

Correspondence to B de las Heras or S Hortelano.

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Competing interests

RL-F, B de las H, BR and SH are inventors on a Spanish patent application on labdane diterpenoids as antitumoral agents. The other authors declared no conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Través, P., López-Fontal, R., Cuadrado, I. et al. Critical role of the death receptor pathway in the antitumoral effects induced by hispanolone derivatives. Oncogene 32, 259–268 (2013). https://doi.org/10.1038/onc.2012.23

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  • DOI: https://doi.org/10.1038/onc.2012.23

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