Abstract 1394: Apoptosis of pancreatic cancer cells after co-treatment with eugenol and tumor necrosis factor-related apoptosis-inducing ligand

Abstract Pancreatic cancer is a refractory cancer with limited treatment options, and resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) poses a significant therapeutic challenge. This study aimed to investigate whether eugenol, the main component of clove oil with known anticancer, anti-inflammatory, and antioxidant properties, could enhance TRAIL sensitivity by upregulating death receptor (DR) expression levels in pancreatic cancer cells. To explore this, we treated pancreatic cancer cells with eugenol and TRAIL, individually and in combination, and evaluated apoptosis and cell proliferation rates. Expression levels of key proteins, including DR5, FLICE-inhibitory protein (FLIP), and p53, were assessed. Additionally, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, and C/EBP-homologous protein (CHOP) involvement were analyzed using siRNA knockdown approaches. Our findings revealed that combined treatment with eugenol and TRAIL significantly increased apoptosis and inhibited cell proliferation compared with eugenol alone. Eugenol upregulated DR5 expression, downregulated the anti-apoptotic protein FLIP, and increased levels of the tumor suppressor protein p53. Furthermore, eugenol induced ROS generation and caused ER stress, with CHOP playing a critical role. CHOP knockdown decreased DR5 expression and reduced the synergistic apoptotic effects of eugenol and TRAIL, confirming the ROS-mediated ER stress-CHOP pathway as a key mechanism. These results demonstrate that eugenol enhances TRAIL-induced apoptosis by upregulating DR5 through ROS-mediated ER stress and CHOP activation, which further enhances ER stress via p53 induction and FLIP downregulation. This suggests that eugenol has the potential to serve as a novel TRAIL sensitizer and offers a promising approach to overcoming TRAIL resistance in pancreatic cancer treatment. Citation Format: Hyun Hee Kim, Dae-Hee Lee. Apoptosis of pancreatic cancer cells after co-treatment with eugenol and tumor necrosis factor-related apoptosis-inducing ligand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1394.