Nature 475, 231–234 (2011)

After malignant transformation, cells show molecular signatures—such as increased levels of reactive oxygen species (ROS)—indicative of stress pathways. To adapt to such persistent stressors, transformed cells rely upon stress response pathways much more than do normal cells. Raj et al. now show that targeting components of the ROS homeostasis network may offer an effective means for killing cancer cells. Using chemical screening, the authors identified the plant natural product piperlongumine as an inducer of cancer cell apoptosis that confers no toxicity to normal cells. Proteomic analysis and in vitro assays revealed that piperlongumine binds and inhibits the activity of glutathione S-transferase pi (GSTPI), a component of a protein complex involved in ROS homeostasis. Measurements of cellular ROS levels revealed that piperlongumine treatment enhances hydrogen peroxide and nitric oxide production in cells with a cancer genotype but not in normal cells; similarly, the compound's effects are abrogated when it is administered together with a reducing agent such as N-acetyl-L-cysteine or when GSTPI is overexpressed. These results support a model in which piperlongumine-induced perturbation of ROS levels leads to selective apoptosis of transformed cells that have become dependent on the ROS stress response. The authors also showed in tumor xenografts and mouse cancer models that piperlongumine has promise for therapeutic applications.