Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems

Piperlongumine (PL), naturally synthesized in long pepper, is known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis. ROS are the primary effector molecules of radiation, and increase of ROS production by pharmacological modulation is known to enhance radioresponse. We therefore investigated the radiosensitizing effect of PL in colorectal cancer cells (CT26 and DLD-1) and CT26 tumor-bearing mice. Firstly, we found that PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase. Secondly, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells, linked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration. Finally, the radiosensitizing effect of PL was verified in vivo. PL improved the tumor response to both single and fractionated radiation, resulting in a significant increase of survival rate of tumor-bearing mice, while it was ineffective on its own. In line with in vitro findings, enhanced radioresponse is associated with inhibition of antioxidant systems. In conclusion, our results suggest that PL could be a potential radiosensitizer in colorectal cancer.