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

Abstract

Cholangiocarcinoma (CCA) is a very aggressive tumor. Te development of a new therapeutic drug for CCA is required. Tis
study aims to evaluate the antitumor efect 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 confrmed by comparing 1
H- and 13C-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. Te phosphorylation of signaling molecules in HuCCT1 cells was detected. To determine the efects 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. Te 1
H- and 13C-NMR data of
THC and CBN were almost identical to those reported in the literature. THC and CBN signifcantly inhibited cell proliferation and
migration and induced apoptosis in HuCCT1 cells. Te 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 signifcantly slower tumor progression and smaller
tumor volumes than control mice. THC and CBN induced apoptosis in CCA by inhibiting the AKT and MAPK pathways. Tese
fndings provide a strong rationale for THC and CBN as therapeutic options for CCA