Apoptosis of Pancreatic Cancer Cells after Co-Treatment with Eugenol and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

Simple Summary Pancreatic cancer is a challenging disease with limited treatment options and poor prognosis. This study aims to investigate whether eugenol, the main component of clove oil, can enhance the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Eugenol is known for its anticancer properties, and we aim to determine if it can increase the expression of death receptors to reduce TRAIL resistance. By exploring the combination of eugenol and TRAIL, we seek to understand how effective this approach is in inducing apoptosis in pancreatic cancer cells. The findings could offer a new strategy for treating pancreatic cancer and provide significant insights into therapeutic approaches for this aggressive disease within the research community.Abstract Pancreatic cancer is a refractory cancer with limited treatment options. Various cancer types are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Eugenol, the main component of clove oil, exhibits anticancer, anti-inflammatory, and antioxidant effects. However, no studies have reported that eugenol increases TRAIL sensitivity by upregulating death receptor (DR) expression. Here, we aimed to investigate eugenol as a potent TRAIL sensitizer. Increased apoptosis and inhibition of cell proliferation was observed in pancreatic cancer cells treated with eugenol and TRAIL compared with those treated with eugenol alone. Eugenol upregulated the expression of DR5, inhibited the FLICE-inhibitory protein (FLIP), an anti-apoptotic protein, and increased p53, a tumor suppressor protein. In addition, eugenol induced the generation of reactive oxygen species (ROS) and caused endoplasmic reticulum (ER) stress. C/EBP-homologous protein (CHOP) knockdown using siRNA decreased the expression of DR5 and reduced the combined effects of eugenol and TRAIL. These results demonstrate that eugenol enhances TRAIL-induced apoptosis by upregulating DR5 through the ROS-mediated ER stress-CHOP pathway, which enhances ER stress by inducing p53 and downregulating FLIP expression. This suggests that eugenol has the potential to treat pancreatic cancer by increasing cell sensitivity to TRAIL.