Breana Boirie
Florida A&M University
Co-Authors: Mounika Aare1, Arvind Bagde1, Sandeep Chary1, Mandip Singh Sachdeva1
1Florida A&M University
Background: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, ranking fourth in cancer-related mortality. Standard treatment with gemcitabine, alone or with nab-paclitaxel, improves drug delivery but remains limited by resistance. Cannabinoid receptors are overexpressed in PDAC, and recent evidence suggests cannabinoids possess anticancer properties, offering a potential strategy to overcome treatment resistance.
Objective: The study aimed to evaluate whether combining standard-of-care chemotherapy with various cannabinoids could improve treatment outcomes in PDAC, particularly by targeting resistance mechanisms linked to KRAS, an oncogene mutated in over 90% of cases.
Methods: Several cannabinoids, including cannabichromene (CBC), cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), and cannabidivarin (CBDV), were initially screened for anticancer activity in MIAPACA-2 and PANC1 cell lines. Selected cannabinoids were combined, and their synergistic effects were assessed using Combination Index values calculated with compusyn software. Additional experiments such as migration study, western blotting and preliminary in-vivo tumor studies were conducted to better understand the molecular mechanisms.
Results: The cytotoxic effects of cannabinoids combined with standard chemotherapeutic agents were evaluated in MiaPaca pancreatic cancer cells. CBC and CBD were tested individually, each demonstrating an IC₅₀ of 4 μM. When used in combination, the IC₅₀ was reduced to 1.98 μM, indicating a synergistic cytotoxic effect.
Nab-paclitaxel, evaluated as a single agent, exhibited potent cytotoxicity with an IC₅₀ of 80 nM. Remarkably, combining CBD+ Nab-paclitaxel further enhanced its efficacy, reducing the IC₅₀ to 6.09 nM. These findings suggest that the incorporation of cannabinoids can significantly enhance the potency of conventional chemotherapeutic agents in the context of pancreatic cancer treatment. Additional experiments focused on the molecular mechanisms underlying these effects. The combination of CBG+CBD significantly downregulated key apoptosis markers. When CBG or CBD was paired with Nab-paclitaxel, there was a pronounced reduction in KRAS expression compared to individual treatments. Western blot analyses further supported these observations by revealing significant downregulation of multiple oncogenic and survival proteins—including survivin, PI3K110, caspase-3, KRAS, Notch1, and SOD2—in the CBG, CBD, and CBG+CBD treatment groups (p < 0.0001). Moreover, in-vivo studies demonstrated that treatments with CBG, CBD, Nab-paclitaxel, and their combinations significantly downregulated KRAS relative to controls (p < 0.0001), with the effects of CBD+ Nab-paclitaxel being comparable (p<0.0149) demonstrating the role of CBD in pancreatic cancer.
Conclusion: Based on these results, combinations of the most promising cannabinoids were assessed, with focus on their impact on KRAS, a critical oncogene mutated in over 90% of PDAC cases and linked to chemoresistance.