Anticancer activity of Δ9-tetrahydrocannabinol and cannabinol in vitro and in human lung cancer xenograft

Objective:

To investigate the effects of Δ⁹-tetrahydrocannabinol, the principal psychoactive compound of Cannabis sativa, and cannabinol, a Δ⁹-tetrahydrocannabinol degradative product, on human non-small cell lung cancer cells.

Methods:

Δ⁹-Tetrahydrocannabinol and cannabinol were tested for anticancer activity in human non-small cell lung cancer (A549) cells. The effects on cell proliferation, apoptosis, and phosphorylation profiles were examined. The effects of Δ⁹-tetrahydrocannabinol and cannabinol on tumor growth were also investigated using a xenograft nude mouse model. Apoptosis and targeted phosphorylation were verified by immunohistochemistry.

Results:

Δ⁹-Tetrahydrocannabinol and cannabinol significantly inhibited cell proliferation and increased the number of apoptotic cells in a concentration-dependent manner. The Δ⁹-tetrahydrocannabinol- and cannabinol-treated cells had lower levels of phosphorylated protein kinase B [AKT (S473)], glycogen synthase kinase 3 alpha/beta, and endothelial nitric oxide synthase compared to the controls. The study of xenograft mice revealed that tumors treated with 15 mg/kg Δ⁹-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly smaller than those of the control mice. The tumor progression rates in mice treated with 15 mg/kg Δ⁹-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly slower than in the control group.

Conclusions:

These findings indicate that Δ⁹-tetrahydrocannabinol and cannabinol inhibit lung cancer cell growth by inhibiting AKT and its signaling pathways, which include glycogen synthase kinase 3 alpha/beta and endothelial nitric oxide synthase.