Cytotoxic and NF-κB-modulating effects of cannabis constituents

Abstract

Cannabinoids have been found to modulate apoptotic signalling and the activation of Nuclear Factor kappa B (NF-κB). Most reports refer to delta9-tetrahydrocannabinol (THC); however, anti-inflammatory effects were also found for other cannabis constituents such as the prenylated flavone cannflavin A1. A systematic comparison of the anti-inflammatory and cytotoxic activities of major cannabinoid and phenolic constituents of cannabis has not, been carried out to date. We have therefore screened THC, CBD, CBG, CBN, cannflavin A/B, and other compounds for cytotoxicity, by measuring mitochondrial viability using a standard MTT assay in three cancer cell lines (HeLa/PC12/J774A.1). The effect on PMA/TNFα-induced NF-κB activation was tested in HeLaluc cells stably transfected with an IL-6 reporter gene. Cannabinoids alone, or in combinations, proved to be more toxic (LC50 <10µM) than non-cannabinoid plant constituents (LC50 >100µM). Interestingly, the cytotoxic effect induced by cannabinoids could be reverted by some of the phenolic compounds. The inhibition of PMA stimulated NF-κB expression by cannabinoids showed to be almost negligible at non toxic concentrations. Unexpectedly, some of the phenolic compounds enhanced the activation of this nuclear factor, which was more pronounced after TNFα activation. The interplay between metabolites from cannabis in the activation/inhibition of NF-κB as well as its modulation by CB1-, CB2- and TRPV1 antagonists is discussed.