R. Sancho, L. de la Vega, G. Appendino
Nov 1, 2003
British Journal of Pharmacology
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‐FADDDN 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‐FADDDN 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.