Marijuana Smoke and Δ9-Tetrahydrocannabinol Promote Necrotic Cell Death but Inhibit Fas-Mediated Apoptosis

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Marijuana smoke shares many components in common with tobacco smoke except for the presence of Δ9-tetrahydrocannabinol (Δ9-THC), the psychotropic compound found only in Cannibis sativa. Δ9-THC has been shown to potentiate smoke-induced oxidative stress and necrotic cell death. In the present study, our objective was to determine the effects of Δ9-THC on the balance between Fas-induced apoptosis and necrosis in A549 lung tumor cells. We found that Fas-induced activation of caspase-3 was inhibited by whole smoke from both tobacco and marijuana cigarettes. Gas-phase smoke, 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 tar being more potent than either tobacco or placebo marijuana tar (lacking Δ9-THC). Δ9-THC also inhibited Fas-induced caspase-3 activity in A549 cells. In contrast, no inhibition was observed when Δ9-THC was incubated with activated caspase-3 enzyme, suggesting that Δ9-THC acts on the cell pathway(s) leading to caspase-3 activation and not directly on enzyme function. Flow cytometry was used to measure the percentage of cells undergoing apoptosis (staining for annexin V) versus necrosis (staining for propidium iodide) and confirmed that both marijuana tar extract and synthetic Δ9-THC inhibit Fas-induced apoptotis while promoting necrosis. These observations suggest that the Δ9-THC contained in marijuana smoke disrupts elements of the apoptotic pathway, thereby shifting the balance between apoptotic and necrotic cell death. This shift may affect both the carcinogenic and immunologic consequences of marijuana smoke exposure.