Opposing Effects of Cannabidiol in Patient-derived Neuroendocrine Tumor, Pheochromocytoma/Paraganglioma Primary Cultures

Context: Treatment options for advanced neuroendocrine tumors (NETs), pheochromocytomas and paragangliomas (PPGLs) are still limited. In recent years, antitumor effects of cannabinoids have been reported; however, there are only very limited data available in NETs or PPGLs. Objective: Investigation of the effects of cannabidiol (CBD) on patient-derived human NET/PPGL primary cultures and on NET/PPGL cell lines. Methods: We established primary cultures derived from 46 different patients with PPGLs (n = 35) or NETs (n = 11) who underwent tumor resection at 2 centers. Treatment of patient primary cultures with clinically relevant doses (5 μM) and slightly higher doses (10 μM) of CBD was performed. Results: We found opposing effects of 5 μM CBD: significant antitumor effects in 5/35 (14%) and significant tumor-promoting effects in 6/35 (17%) of PPGL primary cultures. In terms of antitumor effects, cluster 2-related PPGLs showed significantly stronger responsivity to CBD compared to cluster 1-related PPGLs (P =. 042). Of the cluster 2-related tumors, NF1 PPGLs showed the strongest responsivity (4/5 PPGL primary cultures with a significant decrease in cell viability were NF1-mutated). We also found opposing effects of 10 μM CBD in PPGLs and NETs: significant antitumor effects in 9/33 of PPGL (27%) and 3/11 of NET (27%) primary cultures and significant tumor-promoting effects in 6/33 of PPGL (18%) and 2/11 of NET (18%) primary cultures. Conclusion: We suggest a potential novel treatment option for some NETs/PPGLs but also provide evidence for caution when applying cannabinoids as supportive therapy for pain or appetite management to cancer patients and possibly as health supplements.