Selective killing of cancer cells by a small molecule targeting the stress response to ROS Lakshmi Raj1, Takao Ide1, Aditi U. Gurkar1, Michael Foley2, Monica Schenone2, Xiaoyu Li2, Nicola J. Tolliday2, Todd R. Golub2, Steven A. Carr2, Alykhan F. Shamji2, Andrew M. Stern2, Anna Mandinova1,2, Stuart L. Schreiber2 & Sam W. Lee1,2 Nature Volume: 475, Pages: 231–234, Date published: 14 July 2011 Presenter : Shang-Yu Yeh Commentator : Dr. Nan-Haw Chow Date/Time : 2011/10/06 16:10 -17:00 Location : Room 601, Med College Building Background : In the initiation of carcinogenic processes, cellular stresses (such as, oxidative, DNA damage, replicative, metabolic and proteotoxic stress) lead to the mutations of oncogenes and tumor suppressor genes which are essential for cancer cell surviving. Therefore, cancer cells adapt to cellular stresses make them an apparently different genotype to normal cells. The authors then identify a small molecule, Piperlongumine, which kills cancer cells but not normal cells selectively. They also investigate the mechanism of Piperlongumine–induced apoptosis which is associated with reactive oxygen species (ROS). Objective: To identify a small molecule and demonstrate its mechanism of induce apoptosis selectively though cancer genotype that is changed by ROS stress mainly. Result: The authors used a cell-based small molecule screening and quantitative proteomics approach to find a small molecule, Piperlongumine. By interfering the redox-related oncogene (HRAS) and ROS homeostatic regulators such as Glutathione S transferase pi 1 (GSTP1) and carbonyl reductase (CBR1), Piperlongumine markedly induces the apoptosis and ROS increasing of normal cells with cancer genotype and cancer cells in both wild-type P53 and mutant P53 but not normal cells without cancer genotype. Conclusion: The effect of Piperlongumine on perturbing redox and ROS homeostatic may become a novel strategy for killing cancer cell specifically. References : 1. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and nononcogene addiction. Cell 136, 823–837 (2009). 2. Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS mediated mechanisms: a radical therapeutic approach? Natl Rev. 8, 579–591 (2009).