Radiosensitization of human pancreatic cancer by piperlongumine analogues

A series of piperlongumine derivatives were synthesized. Compounds 9c and 9d enhanced the radiosensitivity of Panc-1 and SW1990 cells with high sensitivity enhancement ratios. They also significantly inhibited tumor growth in pancreatic bi-flank xenograft tumor model. They can induce ROS expression and target Keap1 to up-regulate γ-H2AX to induce DNA damage, G2/M-phase cell cycle arrest, and apoptosis. [Display omitted] Radiotherapy is commonly used to treat advanced pancreatic cancers and can improve survival by 2 months in combination with gemcitabine. However, prognosis and survival improvement remain unsatisfactory, and effective therapies are urgently needed. Piperlongumine has been demonstrated to have therapeutic potentials against various cancers. In this study, we synthesized a series of piperlongumine derivatives and provided evidence that piperlongumine derivatives could be used as effective radiosensitizers in pancreatic cancer. Two compounds enhanced the radiosensitivity of Panc-1 and SW1990 cells. In a pancreatic bi-flank xenograft tumor model, they significantly inhibited tumor growth. Piperlongumine derivatives could induce reactive oxygen species (ROS) expression and regulate the Keap1-Nrf2 protective pathway with enhancement of radiation-induced DNA damage, G2/M-phase cell cycle arrest, and apoptosis. Collectively, our data offer a proof of concept for the use of piperlongumine derivatives as a novel class of radiosensitizers for the treatment of pancreatic cancer.