Marijuana smoke and Delta(9)-tetrahydrocannabinol promote necrotic cell death but inhibit Fas-mediated apoptosis

Marijuana smoke shares many components in common with tobacco smoke except for the presence of Delta (9)-tetrahydrocannabinol (Delta (9)-THC), the psy chotropic compound found only in Cannibis sativa. Delta (9)-THC has been sh own to potentiate smoke-induced oxidative stress and necrotic cell death. I n the present study, our objective was to determine the effects of Delta (9 )-THC on the balance between Fas-induced apoptosis and necrosis in A549 lun g tumor cells. We found that Fas-induced activation of caspase-3 was inhibi ted by whole smoke from both tobacco and marijuana cigarettes. Gas-phase sm oke, which generates high levels of intracellular reactive oxygen species, had no effect on caspase-3 activity. However, particulate-phase smoke (tar) was a potent inhibitor of Fas-induced caspase-3 activity, with marijuana t ar being more potent than either tobacco or placebo marijuana tar (lacking Delta (9)-THC). Delta (9)-THC also inhibited Fas-induced caspase-3 activity in A549 cells. In contrast, no inhibition was observed when Delta (9)-THC was incubated with activated caspase-3 enzyme, suggesting that Delta (9)-TH C acts on the cell pathway(s) leading to caspase-3 activation and not direc tly on enzyme function. Flow cytometry was used to measure the percentage o f cells undergoing apoptosis (staining for annexin V) versus necrosis (stai ning for propidium. iodide) and confirmed that both marijuana tar extract a nd synthetic Delta (9)-THC inhibit Fas-induced apoptotis while promoting ne crosis. These observations suggest that the Delta (9)-THC contained in mari juana smoke disrupts elements of the apoptotic pathway, thereby shifting th e balance between apoptotic and necrotic cell death. This shift may affect both the carcinogenic and immunologic consequences of marijuana smoke expos ure. (C) 2001 Academic Press.