Selective killing of cancer cells with a small molecule targeting stress response to ROS
By Lakshmi Raj, T. Ide, Aditi U. Gurkar, M. Foley, M. Schenone, Xiaoyu Li, N. Tolliday, Todd R. Golub, Steven A. Carr, Alykhan F. Shamji and 4 more. Nature, 2011
962 citations recorded by the source corpus.
Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (e.g., oxidative, replicative, metabolic, proteotoxic, 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 cell genotype may result in a synthetic lethal interaction and selective cancer cell death2. 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 over normal cells. Piperlongumine (PL) increases 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, with little effect on either rapidly or slowly dividing primary normal cells. Significant anti-tumor effects are observed in PL-treated mouse xenograft tumor models, with no apparent toxicity in normal mice. Moreover, PL potently inhibits spontaneously formed malignant breast tumor growth and associated metastases in mice. The results of this study illustrate the ability of a small molecule to induce apoptosis selectively in cells having a cancer genotype by targeting a non-oncogene co-dependency acquired by the expression of the cancer genotype in response to transformation-induced oxidative stress3–5.
Subfields: Organic Chemistry, Pharmacology
View Paper: https://www.semanticscholar.org/paper/a94e96f375f670490c691972f17cb9b6d671e397
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In Organic Chemistry
Citations in the corpus
- Upsides and Downsides of Reactive Oxygen Species for Cancer: The Roles of Reactive Oxygen Species in Tumorigenesis, Prevention, and Therapy (2012, neutral): “Induction of cell death In vitro studies H2O2 Exogenous Lymphoma Capase-3 [ a (114) Exogenous Bladder MEK1/2 [, ERK1/2 [ (59) Caspase-3 [, Caspase-7 [ Apigenin Hepatoma Catalase Y (310) PDT Leukemia Caspase 3 [ (248) Melatonin Leukemia Caspase-3 [, Caspase-8 [ (28) Caspase-9 [ PL Osteosarcoma, breas”
- Targeting Metabolism for Cancer Therapy (2017, background): “…screens for small-molecules that selectively kill transformed cells have identified compounds that reduce glutathione levels (Dolma et al., 2003; Raj et al., 2011; Trachootham et al., 2006), and genetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and…”
- Mitochondrial reactive oxygen species and cancer (2014, background): “In support of this model, several small molecule screens identifying compounds that specifically inhibit growth of transformed cells have converged upon glutathione utilization [110-112].”
- Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress (2018, background): “As an additional negative control, treatment with piperlongumine, an ROS-inducing drug that triggers apoptosis (Raj et al., 2011) rather than lipid ROS-mediated ferroptosis, did not show differentiation-associated sensitivity (Figures S5B and S5C).”
- Target identification with quantitative activity based protein profiling (ABPP) (2017, background): “4), which was found by the group to exhibit selective anticancer properties [57].”
- Understanding the intersections between metabolism and cancer biology (2017, neutral): “Exacerbating oxidative stress potentiates some chemotherapeutic responses (Harris et al., 2015; Raj et al., 2011), and enhances response to radiation therapy (Robbins and Zhao, 2004).”
- Ferroptosis: an iron-dependent form of nonapoptotic cell death. (2012, background): “Our results suggest an underlying similarity between diverse forms of iron-dependent, nonapoptotic death and that the manipulation of ferroptosis may be exploited to selectively destroy RAS mutant tumor cells or to preserve neuronal cells exposed to specific oxidative conditions.”
- PGC1α Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress (2013, positive): “In fact, transformed cells have been shown to be exquisitely more sensitive to ROS-inducing drugs than nontransformed cells (Trachootham et al., 2006; Raj et al., 2011).”