Effects of tetrahydrocannabinols on human oral cancer cell proliferation, apoptosis, autophagy, oxidative stress, and DNA damage

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Abstract
Objective
Cannabinoids, including delta-8- and delta-9-tetrahydrocannabinol (THC) have a palliative care impact and may therefore be beneficial against cancer. The aim of this study was to investigate the effect of Δ9-THC and Δ8-THC on oral cancer cell behaviors.

Design
The Ca9-22 oral cancer cells were cultured in the presence or not of various concentrations of Δ9-THC and Δ8-THC for different times. The cultures were then used to measure cell viability/proliferation, apoptosis, autophagy, oxidative stress, antioxidant activity, and inhibition of signaling pathways MAP-Kinase, NF-κB, and β−catenin.

Results
Both cannabinoids were found to decrease cell viability/proliferation by blocking the cell cycle progression from the S to the G2/M phase and enhancing their apoptosis and autophagy. Δ9-THC and Δ8-THC also suppressed the migration/invasion by inhibiting epithelial-mesenchymal transition markers, such as E-cadherin, in addition to decreasing reactive oxygen species (ROS) production and increasing glutathione (GSH) and the expression of mtMP. Δ9-THC and Δ8-THC also downregulated cyclin D1, p53, NOXA, PUMAα, and DRAM expressions but increased p21 and H2AX expression.

Conclusion
We demonstrated that cannabinoids (Δ9-THC and Δ8-THC) were able to decrease oral cancer cell growth through various mechanisms, including apoptosis, autophagy, and oxidative stress. These results suggest a potential use of these molecules as a therapy against oral cancer.