Carvedilol Upregulates Inflammatory Factors to Enhance Paclitaxel Sensitivity in Paclitaxel‐Resistant Gastric Cancer AGS Cells: Influences on β‐Arrestin‐2/cGAS‐STING Axis

Inflammation plays a critical role in tumor progression and drug resistance. Our previous research has repurposed carvedilol (CVL) to re-sensitize paclitaxel (PTX)-resistant gastric cancer AGS Cells (AGS-Rpac) to PTX. This study aimed to evaluate the effects of combined CVL and PTX therapy on the modulation of inflammatory mediators and their associated signaling pathways. AGS-Rpac cells were treated with specified concentrations of PTX and CVL. Levels of IL-1β and TNF-α were measured. The expression levels of nuclear factor kappa B (NF-κB p65), NLR family pyrin domain containing 3 (NLRP3), as well as the β2-adrenergic receptor (β2-AR), β-arrestin-2, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), were assessed by western blotting. CVL alone, and particularly PTX and CVL + PTX treatments, prompted a significant increase in NLRP3, NF-κB p65, IL-1β, and TNF-α inflammatory factors compared to the control. β2-AR expression was decreased in CVL-treated cells compared to other groups (p < 0.001). β-Arrestin-2 and cGAS levels were increased in CVL monotherapy, whereas they were reduced in the PTX-treated cells compared to the control. These protein levels were restored to near-control levels with combination therapy. STING expression was upregulated in the control and CVL groups. The diminished levels of STING in PTX-treated cells were slightly increased in combination therapy. The combination of PTX and CVL significantly increased levels of inflammatory factors. CVL appears to recruit β-arrestin-2 to β-adrenergic receptors, which, in turn, activate the cGAS-STING pathway and induce the production of inflammatory factors.