Carvedilol sensitizes paclitaxel-resistant gastric cancer AGS cells to paclitaxel: influences on apoptotic regulators, Notch, PI3K/AKT, ERK1/2 signaling pathways, and miR-34a expression

The occurrence of drug resistance is a leading cause of successful therapy failure in gastric cancer patients. This study aimed to investigate the potential resensitizing effect of carvedilol (CVL) in paclitaxel (PTX) resistant gastric cancer (AGS-Rpac) cells. AGS-Rpac cells were co-treated with various concentrations of PTX and CVL. Cellular viability was measured, and the combination index was calculated. The formation of reactive oxygen species (ROS) and the induction of apoptosis were measured. The expressions of key apoptotic genes, the Notch signaling pathway, and miR-34a were investigated. Protein levels of essential ABC transporters, apoptotic regulators, Notch, PI3K/AKT, and ERK1/2 signaling pathways were also assessed. CVL displayed a distinguished synergistic effect. Co-treatment with CVL and PTX significantly reduced the viability of AGS-Rpac cells and increased intracellular ROS levels. A significant increase in early and late apoptotic cells was observed in the combination-treated group. Modulations in the expression profiles of the BCL-2 and CASP-3 genes favored apoptosis. The expression levels of Notch1, HES1, and HEY1 genes and proteins were reduced following treatment with CVL alone and in combination. The diminished levels of miR-34a were upregulated following treatment with CVL alone, and more significantly in combination-treated groups. The levels of P-gp, MRP-1, cleaved-CASP3, P53, HIF-1α, PI3K, p-AKT, and p-ERK1/2 decreased while the pro-CASP3 level was diminished in CVL + PTX-treated cells. Our findings suggest that CVL could be repurposed as a co-treatment candidate, capable of overcoming PTX resistance, inducing apoptosis, enhancing miR-34a expression, reducing the expression of efflux transporters, and inhibiting essential survival signaling pathways.