Pancreatic cancer is one of the most aggressive forms of cancer with a relatively high chance of metastasis and a relatively low successrate of surgical resection. Preclinical evidence suggests the endocannabinoid system is involved in the pathogenesis of pancreatic cancer and cannabinoids such as THC have anti-tumoral effects. Also the combination of chemotherapy and cannabinoids appears beneficial and synergystic.
In one study, THC effectively killed pancreatic cancer cells (in Panc1, Capan2, BxPc2 and MIA PaCa-2 cell lines) at 2 μM and higher concentrations (Carracedo et al., 2006). The authors found that both CB1 and CB2 were upregulated in cancer cells. Apoptosis was CB2-dependent (but see Fogli et al.) In mice, 15 mg/kg/d THC induced tumor cell-specific apoptosis and significantly reduced tumor growth (Carracedo et al., 2006).
In human pancreatic cancer cells (MIA PaCa-2) various agonists and antagonists for CB1 and CB2 were found to induce apoptosis (Fogli et al., 2006). These effects appeared to be CB1 and CB2 independent and are counterintuitive but they do suggest the involvement of the endocannabinoid system in the pathogenesis of pancreatic cancer.
In human patients, high CB1 expression in pancreatic cancer cells was associated with reduced survival. Similarly, low levels of endocannabinoid-degrading enzyme FAAH and MAGL were associated with reduced survival. Interestingly, Anandamide and 2AG levels were unchanged in pancreatic cancer. Finally, contrary to CB1 expression in cancer cells, low CB1 in nervous tissue was associated with increased cancer pain, but also increased survival (Michalski et al., 2008). The mechanistic value of these correlations remains to be elucidated.
The anti-tumoral effect of standard anti-cancer drug Gemcitabine was greatly enhanced by use of CB1 and CB2 agonists in both cell lines and tumor xenografts in mice (Donadelli et al., 2011), suggesting synergy between classical chemotherapy and cannabinoid-based treatment.
Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzmán, M., Velasco, G., and Iovanna, J.L. (2006). cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. cancer Res. 66, 6748–6755.
Dando, I., Donadelli, M., Costanzo, C., Dalla Pozza, E., D’Alessandro, A., Zolla, L., and Palmieri, M. (2013). cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis. 4, e664.
Donadelli, M., Dando, I., Zaniboni, T., Costanzo, C., Dalla Pozza, E., Scupoli, M.T., Scarpa, A., Zappavigna, S., Marra, M., Abbruzzese, A., et al. (2011). Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis. 2, e152.
Fogli, S., Nieri, P., Chicca, A., Adinolfi, B., Mariotti, V., Iacopetti, P., Breschi, M.C., and Pellegrini, S. (2006). cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 580, 1733–1739.
Michalski, C.W., Oti, F.E., Erkan, M., Sauliunaite, D., Bergmann, F., Pacher, P., Batkai, S., Müller, M.W., Giese, N.A., Friess, H., et al. (2008). cannabinoids in pancreatic cancer: correlation with survival and pain. Int. J. cancer 122, 742–750.