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.
The CB1/VR1 agonist arvanil induces apoptosis through an FADD/caspase-8-dependent pathway.
Di Marzo V;
2003
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
