Paeoniflorin Induces ER Stress-Mediated Apoptotic Cell Death by Generating Nox4-Derived ROS under Radiation in Gastric Cancer.

Gastric cancer is one of the most prevalent cancer types worldwide, and its resistance to cancer therapies, such as chemotherapy and radiotherapy, has made treating it a major challenge. Paeoniflorin (PF) is one potential pharmacological treatment derived from paeony root. However, in cancer, the molecular mechanisms and biological functions of PF are still unclear. In the present study, we found that PF exerts anti-tumor effects in vivo and in vitro and induces apoptotic cell death through ER stress, calcium (Ca), and reactive oxygen species (ROS) release in gastric cancer cells. However, ROS inhibition by DPI and NAC blocks cell death and the PERK signaling pathway via the reduction of Nox4. Moreover, PF triggers a synergistic inhibitory effect of the epithelial-mesenchymal transition (EMT) process under radiation exposure in radiation-resistant gastric cancer cells. These findings indicate that PF-induced Ca and ROS release overcomes radioresistance via ER stress and induces cell death under radiation in gastric cancer cells. Therefore, PF, in combination with radiation, may be a powerful strategy for gastric cancer therapy.