INDUCTION OF APOPTOSIS BY VANILLOID COMPOUNDS DOES NOT REQUIRE DE-NOVO GENE-TRANSCRIPTION AND ACTIVATOR PROTEIN-1 ACTIVITY

The vanilloid compounds, capsaicin and resiniferatoxin, are quinone an alogues that inhibit the NADH-plasma membrane electron transport syste m and induce apoptosis in transformed cells, Because disruption of the mitochondrial transmembrane potential (Delta Psi(m)) is a common meta bolic alteration in all apoptotic processes, we have evaluated the rol e of mitochondrial permeability transition in apoptosis induced by van illoids in Jurkat cells. Using a cytofluorimetric approach, we have de termined that DNA nuclear loss induced by vanilloids is preceded by an increase of the production of reactive oxygen species (ROS) and by a subsequent Delta Psi(m) dissipation in T-cell lines, Overexpression of Bcl-2 and pretreatment with either the immunosuppressant cyclosporin A or the glutathione precursor N-acetyl-L-cysteine blocked Delta Psi(m ) disruption and apoptosis, but not the generation of ROS induced by t hese compounds. Capsaicin and resiniferatoxin were found to activate b oth isoforms of c-jun-NH2-kinase (JNK), with a maximal activity after 30 min of treatment, Despite the activation of JNK, there was no induc tion of activator protein 1 (AP-1) activity as determined by gel shift assay or of induction of an AP-1-responsive reporter. On the other ha nd, vanilloids did not signal for c-Raf kinase and extracellular signa l-regulated kinases 1 and 2. We suggest that ROS generation by inhibit ion of the NADH-dependent plasma membrane electron transport system re sulted in the oxidation of mitochondrial megachannel pores that allows for the disruption of Delta Psi(m) and apoptosis, and that AP-1 activ ation is not required for vanilloid-induced apoptosis.