Abstract
1. 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. 2. 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. 3. 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. 4. 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. 5. 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.
Original language | English |
---|---|
Pages (from-to) | 1035-1044 |
Number of pages | 10 |
Journal | British Journal of Pharmacology |
Volume | 140 |
Issue number | 6 |
DOIs | |
Publication status | Published - Nov 2003 |
Keywords
- Adaptor proteins, Signal transducing
- Apoptosis
- Capsaicin
- Carrier proteins
- Caspase 8
- Caspase inhibitors
- Caspases
- Cells, Cultured
- Cysteine proteinase inhibitors
- DNA fragmentation
- Dose-response relationship, Drug
- Fas ligand protein
- Fas-associated death domain protein
- Humans
- In situ Nick-end labeling
- Jurkat cells
- Membrane glycoproteins
- Models, Biological
- Reactive oxygen snabinoid, CB1pecies
- Receptor, Cannabinoid, CB1
- Receptors, Drug
- Signal transduction
- T-lymphocytes
- Time factors
- Transcription, Genetic