30/09/2026
Background
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, driven in part by persistent activation of pro-survival pathways such as STAT3 and NF-ÎşB.
Aim
Cannabidiol (C*D), a non-psychoactive phytocannabinoid, has emerged as a potential anti-cancer agent; however, its mechanisms in NSCLC remain incompletely defined. In particular, C*D has not been systematically investigated for its ability to simultaneously suppress both constitutive and inducible STAT3/NF-ÎşB activation, while coordinating apoptosis and autophagy in NSCLC. Furthermore, its role as a chemosensitizer in combination with paclitaxel remains to be validated in vivo.
Methods
Human NSCLC cell lines (A549, PC9, and H1299) were treated with cannabidiol (C*D), alone or in combination with paclitaxel. Apoptosis and autophagy were evaluated via caspase-3/7 activity, Western blotting, and immunocytochemistry. The effects of C*D on STAT3 and NF-ÎşB signaling were assessed using EMSA, luciferase reporter assays, and nuclear translocation analysis. Anti-tumor efficacy was further validated in a xenograft mouse model.
Results
Here, we demonstrate that C*D reduced cell viability in NSCLC cells (A549 and PC9), while showing less cytotoxicity in normal lung fibroblasts. Mechanistically, C*D induced apoptosis and autophagy and suppressed STAT3 and NF-κB activation at the levels of phosphorylation, nuclear localization, and transcriptional activity. These effects were also observed in inducible signaling models using IL-6–stimulated H1299 cells. Importantly, C*D enhanced the efficacy of paclitaxel, a commonly used chemotherapeutic agent, by synergistically inducing apoptosis and autophagy and further suppressing STAT3/NF-κB signaling. In a xenograft mouse model, C*D treatment significantly reduced tumor growth without affecting body weight, and combination therapy with paclitaxel led to the most pronounced tumor suppression. Tumor tissue analyses confirmed that C*D downregulated phosphorylated STAT3 and p65, reduced proliferation marker Ki-67, and increased expression of cleaved PARP, LC3 II, and other cell death-associated proteins.
Conclusion
Our findings provide preclinical evidence that C*D exerts potent anti-tumor activity in NSCLC by coordinating inhibition of oncogenic signaling and activation of programmed cell death pathways. To our knowledge, this study provides evidence that C*D concurrently inhibits STAT3 and NF-ÎşB signaling, affecting both constitutive and inducible activation in NSCLC, and enhances paclitaxel efficacy in vivo, thereby establishing a novel mechanistic and translational basis for its therapeutic potential. These results support the therapeutic effect of C*D as a potential adjuvant in lung cancer treatment.
Full Article: https://www.sciencedirect.com/science/article/abs/pii/S094471132600721X?via%3Dihub
