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The CB1/VR1 agonist arvanil induces apoptosis through an FADD/caspase‐8‐dependent pathway
Author(s) -
Sancho Rocío,
De La Vega Laureano,
Appendino Giovanni,
Di Marzo Vincenzo,
Macho Antonio,
Muñoz Eduardo
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705532
Subject(s) - jurkat cells , fadd , apoptosis , microbiology and biotechnology , programmed cell death , dna fragmentation , death domain , biology , chemistry , apoptotic dna fragmentation , caspase , t cell , biochemistry , immunology , immune system
Arvanil ( N ‐arachidonoylvanillamine), a nonpungent capsaicin–anandamide hybrid molecule, has been shown to exert biological activities through VR1/CB1‐dependent and ‐independent pathways. We have found that arvanil induces dose‐dependent apoptosis in the lymphoid Jurkat T‐cell line, but not in peripheral blood T lymphocytes. Apoptosis was assessed by DNA fragmentation through cell cycle and TUNEL analyses. Arvanil‐induced apoptosis was initiated independently of any specific phase of the cell cycle, and it was inhibited by specific caspase‐8 and ‐3 inhibitors and by the activation of protein kinase C. In addition, kinetic analysis by Western blots and fluorimetry showed that arvanil rapidly activates caspase‐8, ‐7 and ‐3, and induces PARP cleavage. The arvanil‐mediated apoptotic response was greatly inhibited in the Jurkat‐FADD DN cell line, which constitutively expresses a negative dominant form of the adapter molecule Fas‐associated death domain (FADD). This cell line does not undergo apoptosis in response to Fas (CD95) stimulation. Using a cytofluorimetric approach, we have found that arvanil induced the production of reactive oxygen species (ROS) in both Jurkat‐FADD + and Jurkat‐FADD DN cell lines. However, ROS accumulation only plays a residual role in arvanil‐induced apoptosis. These results demonstrate that arvanil‐induced apoptosis is essentially mediated through a mechanism that is typical of type II cells, and implicates the death‐inducing signalling complex and the activation of caspase‐8. This arvanil‐apoptotic activity is TRPV1 and CB‐independent, and can be of importance for the development of potential anti‐inflammatory and antitumoral drugs.British Journal of Pharmacology (2003) 140 , 1035–1044. doi: 10.1038/sj.bjp.0705532