Anti-proliferative and apoptotic effect of cannabinoids on human pancreatic ductal adenocarcinoma xenograft in BALB/c nude mice model

Abstract

Human pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal tumor of the exocrine pancreas. Cannabinoids extracted from the hemp plant Cannabis sativa have been suggested as a cancer therapy due to their anti-tumor effects on several human tumors. However, the anti-tumor effect of cannabinoids on human PDAC is still understudied. Therefore, the objective of the current study is to study the inhibition of proliferation and the induction of apoptosis potencies of cannabinoids in PDAC xenograft nude mice model. The human PDAC cell line (Capan-2) was subcutaneously injected into twenty-five nude mice. After tumor reached 200 mm3 in volume, mice were randomly divided into five groups (5 mice/group), following: negative control (NC) (daily gavaged of sesame oil), positive control (PC) (intraperitoneal administration of 5-fluorouracil at 20 mg/kg body weight (BW), three-time/week), and cannabinoid-treated groups (daily gavaged of THC:CBD (1:6) solution at 1, 5, and 10 mg/kg BW for 30 days, respectively). The findings showed that THC:CBD (1:6) significantly decreased the mitotic cells and mitotic/apoptotic ratio, while the apoptotic cells were dramatically increased compared to the NC group. Parallelly, THC:CBD (1:6) significantly reduced the protein expression level of Ki-67 and PCNA relative to the NC group. Interestingly, THC:CBD (1:6) upregulated BAX, BAX/BCL-2 ratio, and Caspase-3 expression level, meanwhile, downregulated BCL-2 expression level and could not change Caspase-8 expression level relative to the NC group. These findings suggest that cannabinoid solution (THC:CBD at 1:6) could inhibit proliferation and induce apoptosis in human PDAC xenograft models. Cannabinoids, including THC:CBD, should be further studied for use as the potent PDCA therapeutic agent in humans.