The Combination of Δ9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins

Abstract:

Phytocannabinoids represent a promising approach in glioblastoma therapy. Previous work
has shown that a combined treatment of glioblastoma cells with submaximal effective concentrations
of psychoactive ∆
9
-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD) greatly
increases cell death. In the present work, the glioblastoma cell lines U251MG and U138MG were used
to investigate whether the combination of THC and CBD in a 1:1 ratio is associated with a disruption
of cellular energy metabolism, and whether this is caused by affecting mitochondrial respiration.
Here, the combined administration of THC and CBD (2.5 µM each) led to an inhibition of oxygen
consumption rate and energy metabolism. These effects were accompanied by morphological changes
to the mitochondria, a release of mitochondrial cytochrome c into the cytosol and a marked reduction
in subunits of electron transport chain complexes I (NDUFA9, NDUFB8) and IV (COX2, COX4).
Experiments with receptor antagonists and inhibitors showed that the degradation of NDUFA9
occurred independently of the activation of the cannabinoid receptors CB1
, CB2 and TRPV1 and of
usual degradation processes mediated via autophagy or the proteasomal system. In summary, the
results describe a previously unknown mitochondria-targeting mechanism behind the toxic effect of
THC and CBD on glioblastoma cells that should be considered in future cancer therapy, especially in
combination strategies with other chemotherapeutics