Journal Article

Selective killing of cancer cells by a small molecule targeting the stress response to ROS

Raj, Lakshmi, Stern, Andrew M., Shamji, Alykhan F., Golub, Todd R., Foley, Michael, Ide, Takao, Carr, Steven A., Li, Xiaoyu, Gurkar, Aditi U., Schenone, Monica, Schreiber, Stuart L., Tolliday, Nicola J., Lee, Sam W., Mandinova, Anna

2011

Overview

ROS-mediated anticancer compound A chemical screen has identified a small molecule, piperlongumine (PL), as a compound that induces selective killing of cancer cells. Piperlongumine acts by increasing reactive oxygen species (ROS) levels in cancer cells. Although it is active against a number of tumour models in vivo irrespective of p53 status, it does not affect normal tissues, including rapidly proliferating non-tumour cells. This work suggests a novel strategy for eradicating cancer cells by targeting the ROS stress-response pathway, but further work will be needed to identify determinants of piperlongumine sensitivity in a wider range of cancers. Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage) 1 . Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells 2 . Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress 3 , 4 , 5 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/92/613 / 692/699/67/1059/602 / Animals / Apoptosis / Apoptosis - drug effects / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Cell Line / Cell Line, Tumor / Cell Transformation, Neoplastic / Cells / Comet Assay / Deregulation / Dioxolanes - adverse effects / Dioxolanes - chemistry / Dioxolanes - pharmacology / DNA Damage - drug effects / Genotype / Humanities and Social Sciences / Kinases / letter / Mice / multidisciplinary / Mutation / Neoplasm Metastasis - drug therapy / Neoplasm Metastasis - pathology / Oxidative stress / Oxidative Stress - drug effects / Proteins / Reactive Oxygen Species - metabolism / Rodents / Science / Small Molecule Libraries - chemistry / Xenograft Model Antitumor Assays