Cancer cell survival appears partly dependent on antioxidative enzymes, whose expression is regulated by the Keap1-Nrf2 pathway, to quench potentially toxic reactive oxygen species (ROS) generated by their metastatic transformation. Piperlongumine, isolated from the Piper longum L. plant, is a small molecule that selectively increases the level of reactive oxygen species (ROS) and apoptosis in cancer cells but not in normal cells. At concentrations less than 15 μM, piperlongumine induces cell death, upregulating proapoptotic genes, and repressing pro-survival genes. In established bladder, breast, lung, and melanoma tumor xenografts in mice, piperlongumine administered daily at 2.4 mg/kg for 2 weeks inhibits tumor growth and angiogenesis. Piperlongumine increases ROS in both cancer cells and normal cells engineered to have a cancer geneotype by selectively binding to proteins known to regulate redox and ROS homeostasis. Previously, piperlongumine has been used as a crude treatment to improve poor blood circulation. It affects platelet function in rabbits by inhibiting platelet aggregation induced by the thromboxane A2 agonist U-46619 with a Ki value of 6.8 μM.
