Targeting multiple cannabinoid anti‐tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer

Background and Purpose The psychoactive cannabinoid Δ 9 ‐tetrahydrocannabinol ( THC ) and the non‐psychoactive cannabinoid cannabidiol ( CBD ) can both reduce cancer progression, each through distinct anti‐tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti‐tumour pathways. Experimental Approach To measure breast cancer cell proliferation/viability and invasion, MTT and B oyden chamber assays were used. Modulation of reactive oxygen species ( ROS ) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using W estern analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo . Key Results CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down‐regulating the transcriptional regulator I d1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co‐target cannabinoid anti‐tumour pathways ( CBD ‐ and THC ‐associated) and discovered the compound O ‐1663. This analogue inhibited I d1, produced a marked stimulation of ROS , up‐regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo . Conclusions and Implications O ‐1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti‐tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer.