Cannabigerol Potentiates Chemotherapy Through Synergistic Suppression of Tumor-Promoting Signaling in Pancreatic Cancer

Breana Boirie, PharmD
Florida A&M University

Co-authors: Breana Boirie¹, Mounika Aare¹, Sandeep Chary¹, Mandip Sachdeva^1
1Florida A&M University

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor survival and limited therapeutic options. Although gemcitabine (GEM) and nab-paclitaxel (NAB-PTX) are standard therapies, their therapeutic efficacy is frequently compromised by chemoresistance. Cannabigerol (CBG), a non-intoxicating cannabinoid, has demonstrated antitumor and chemosensitizing properties; however, its potential to enhance the efficacy of standard PDAC chemotherapy remains unclear.

Objective: This study evaluated the anticancer efficacy of CBG alone and in combination with GEM and NAB-PTX and investigated the cellular and molecular mechanisms underlying CBG-mediated therapeutic enhancement in pancreatic cancer models.

Methods: CBG, GEM, and NAB-PTX were evaluated in MIAPaCa-2 and PANC-1 cells utilizing 2D/3D cytotoxicity assays, combination index analysis, and assessments of apoptosis, migration, and cell cycle progression. Mitochondrial dysfunction, oxidative stress, and tumor-associated signaling pathways were evaluated to characterize the mechanisms underlying the combination’s efficacy.  in vivo efficacy was evaluated using a PANC-1 xenograft model.

Results: Cytotoxicity studies demonstrated that CBG markedly potentiated the cytotoxic activity of GEM and NAB-PTX, with the triple combination producing enhanced cytotoxicity, reducing IC₅₀ values to 6.53 ± 0.0072 nM in MIAPaCa-2 cells and 427 ± 0.07 nM in PANC-1 cells. Combination index analysis demonstrated strong synergistic interactions with CI values ranging from 0.10–0.35 and 0.40–0.73, respectively. CBG enhanced chemotherapy-induced cell-cycle disruption, potentiating GEM-induced S-phase arrest and NAB-PTX-induced G2/M arrest. The triple combination significantly reduced migratory capacity compared with CBG+GEM and CBG+NAB-PTX (p < 0.0001 Additionally, the triple combination treatment induced pronounced mitochondrial dysfunction and oxidative stress, characterized by mitochondrial depolarization and increased reactive oxygen species generation. Western blot analysis demonstrated reduced KRAS expression and suppression of MAPK and PI3K/AKT survival signaling across CBG-based treatments (p < 0.0001). The triple combination further downregulated vimentin, p-NF-κB, 5-HT1B, and 5-HT1D (p < 0.0001). In vivo, the triple combination of CBG (100 mg/kg), GEM (12.5 mg/kg), and NAB-PTX (5 mg/kg) produced the most durable tumor-growth control, with suppression maintained through 52 days compared with CBG+GEM (51 days), CBG+NAB-PTX (18 days), GEM (35 days), CBG (21 days), and NAB-PTX (11 days). Consistent with the antitumor response, the triple combination significantly downregulated KRAS, VEGF-A, and p-NF-κB expression (p < 0.0001). CBG+GEM additionally reduced KRAS, GPX4, p-NF-κB, and 5-HT1D expression, whereas CBG+NAB-PTX decreased KRAS and p-NF-κB expression (p < 0.0001), supporting modulation of multiple tumor-promoting pathways by CBG-based combination therapy.

Conclusions: These findings identify CBG as a potential chemosensitizing cannabinoid that enhances the antitumor activity of GEM and NAB-PTX through synergistic cytotoxicity, mitochondrial and oxidative stress, and suppression of KRAS-associated survival signaling. Collectively, these findings support CBG-based combination therapy as a promising strategy to overcome therapeutic resistance and improve chemotherapy efficacy in PDAC.