Runaway ROS as a selective anticancer strategy.

The majority of cancer therapies target macromolecules important for general cell survival, such as DNA, topoisomerase, and tubulin (e.g. , cisplatin, doxorubicin, and paclitaxel, respectively). While these agents are effective at killing many types of cancer cells, they also affect rapidly dividing normal cells, such as the intestinal lining and bone marrow, resulting in dose limiting toxicities that reduce efficacy against many solid tumors and metastatic disease. A goal of personalized therapy as applied to cancer is to understand the precise defects in the cancer cell, which may only be present in one particular type of cancer and/or a small subset of patients, and to have drugs that exploit these differences. A small number of such cancer-specific therapies exist. These treatments commonly target a unique characteristic of cancer, such as a translocation, mutation, or a protein with elevated expression. The poster child for this approach is imatinib (Gleevec), which inhibits the tyrosine kinase domain of the Bcrabl protein, the product of a translocation between chromosomes 9 and 22 often observed in patients with chronic myeloid leukemia. Analogous success stories have appeared, including gefitinib (Iressa), which inhibits a mutated version of the epidermal growth factor receptor (EGFR) protein found in some non-small-cell lung cancers, and trastuzumab (Herceptin), a monoclonal antibody that targets the Her2/neu receptor that is overexpressed in some breast cancers. As impressive as these success stories are, identifying enough of these types of compounds to cover the diversity of differentially expressed cancer targets is a daunting task. Ideally, compounds could be identified that are capable of killing cancer regardless of tissue origin or cancer subtypes, as is seen with cytotoxins, but with the cancer specificity observed with more personalized therapies, such as those described above. In a recent issue of Nature, Raj et al. disclose a compound that kills cancer cells of various origins in a highly specific manner over noncancerous cells. They identified this compound using a phenotypic screen, demonstrated its selectivity for cancer cells and efficacy in murine tumor models, and discovered the targets of the compound using a combination of stable isotope labeling with amino acids in cell culture (SILAC) and quantitative proteomics. The phenotypic screen identified compounds that increase expression of a luciferase reporter gene that is located behind a p53-activated promoter for a known proapoptotic gene (Scheme 1a). From this screen, pi-