Antitumor Effects of Delta (9)-Tetrahydrocannabinol and Cannabinol on Cholangiocarcinoma Cells and Xenograft Mouse Models

Cholangiocarcinoma (CCA) is a very aggressive tumor. The development of a new therapeutic drug for CCA is required. This study aims to evaluate the antitumor effect of ∆(9)-tetrahydrocannabinol (THC), the major psychoactive component of marijuana (Cannabis sativa), and cannabinol (CBN), a minor, low-psychoactive cannabinoid, on CCA cells and xenograft mice. THC and CBN were isolated, and their identities were confirmed by comparing (1)H- and (13)C-NMR spectra and mass spectra with a database. Cell proliferation, cell migration, and cell apoptosis assays were performed in HuCCT1 human CCA cells treated with THC or CBN. The phosphorylation of signaling molecules in HuCCT1 cells was detected. To determine the effects of THC and CBN in an animal model, HuCCT1 cells were inoculated subcutaneously into nude mice. After the tumors reached an appropriate size, the mice were treated with THC or CBN for 21 days. Tumor volumes were monitored and calculated. The (1)H- and (13)C-NMR data of THC and CBN were almost identical to those reported in the literature. THC and CBN significantly inhibited cell proliferation and migration and induced apoptosis in HuCCT1 cells. The phosphorylation of AKT, GSK-3α/β, and ERK1/2 decreased in HuCCT1 cells treated with THC or CBN. CCA xenograft mice treated with THC showed significantly slower tumor progression and smaller tumor volumes than control mice. THC and CBN induced apoptosis in CCA by inhibiting the AKT and MAPK pathways. These findings provide a strong rationale for THC and CBN as therapeutic options for CCA.