Cannabigerol Induces Autophagic Cell Death by Inhibiting EGFR-RAS Pathways in Human Pancreatic Ductal Adenocarcinoma Cell Lines

• Published in: International journal of molecular sciences 2024-02, Vol.25 (4), p.2001
• Main Authors: Zeppa, Laura, Aguzzi, Cristina, Morelli, Maria Beatrice, Marinelli, Oliviero, Giangrossi, Martina, Luongo, Margherita, Amantini, Consuelo, Santoni, Giorgio, Nabissi, Massimo
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Apoptosis; Autophagic Cell Death; Autophagy; Biochemistry; Cancer; Cannabidiol; cannabigerol; Cannabinoids; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Cell death; Cell growth; Cell Line, Tumor; chemo-resistance; Chemotherapy; Cytotoxicity; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug dosages; ErbB Receptors; Health aspects; Humans; Kinases; Marijuana; Medical prognosis; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Phosphorylation; Proteins; RAS pathways; Treatment resistance
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25042001

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent infiltrating type of pancreatic cancer. The poor prognosis associated with this cancer is due to the absence of specific biomarkers, aggressiveness, and treatment resistance. PDAC is a deadly malignancy bearing distinct genetic alterations, the most common being those that result in cancer-causing versions of the KRAS gene. Cannabigerol (CBG) is a non-psychomimetic cannabinoid with anti-inflammatory properties. Regarding the anticancer effect of CBG, up to now, there is only limited evidence in human cancers. To fill this gap, we investigated the effects of CBG on the PDAC cell lines, PANC-1 and MIAPaCa-2. The effect of CBG activity on cell viability, cell death, and EGFR-RAS-associated signaling was investigated. Moreover, the potential synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. MTT was applied to investigate the effect of CBG on PDAC cell line viabilities. Annexin-V and Acridine orange staining, followed by cytofluorimetric analysis and Western blotting, were used to evaluate CBG's effect on cell death. The modulation of EGFR-RAS-associated pathways was determined by Western blot analysis and a Milliplex multiplex assay. Moreover, by employing the MTT data and SynergyFinder Plus software analysis, the effect of the combination of CBG and chemotherapeutic drugs was determined.