Spotlight pubs.acs.org/crt
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SYSTEMATIC SCREEN OF CHEMOTHERAPEUTICS IN DROSOPHILA STEM CELL TUMORS
In the battle against cancer, a recurring difficulty is chemotherapy drug resistance. This problem occurs when a drug kills susceptible cells in a tumor but leaves cells with reduced sensitivity to the drug unscathed. In some cases, the latter type of cell may include cancer stem cells (CSCs), a rare class of cells previously identified in brain, breast, and colorectal cancers. CSCs, which are emerging as targets for new anticancer drug development, are highly sensitive to cues in their microenvironment that trigger their division, differentiation, or death. Although drugs that act directly on CSCs have been identified using standard in vitro screening of cultured CSCs, such screening precludes consideration of the role of the microenvironment in stimulating CSC proliferation. Consequently, a research team led by Norbert Perrimon and Michele Markstein endeavored to develop an in vivo protocol for screening stem cells in their native microenvironment that could possibly enable further drug lead identification ((2014) PNAS, 111, 4530−4535). The team engineered a strain of Drosophila to generate fluorescent and chemiluminescent signals in inducible CSC-initiated intestinal tumors. This allowed the team to visually quantify tumor growth or death without dissection in fruit flies fed chemotherapeutic-laced food, enabling the high-throughput screening of over 6 000 compounds. To the authors’ surprise, they discovered that a small subset of known chemotherapeutics that could reduce the growth of induced Drosophila intestinal tumors actually stimulated the proliferation of wild-type intestinal CSCs. From their results, the authors conclude that the impact of a drug on both the isolated CSCs and their microenvironment is equally important to consider during treatment and drug discovery. Heidi A. Dahlmann
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COMPREHENSIVE MOLECULAR CHARACTERIZATION OF UROTHELIAL BLADDER CARCINOMA
Urothelial bladder carcinoma is responsible for about 150 000 deaths per year worldwide, but despite its frequency and morbidity, the standard treatment, cisplatin-based chemotherapy and surgery, has not changed over the last 30 years. A major obstacle to the development of better therapies for any type of cancer is the lack of information about suitable targets that are specific to the disease. To combat this problem, The Cancer Genome Atlas (TCGA) Research Network has undertaken the task of characterizing the genomes of and gene expression in dozens of cancer types in order to enable improving cancer prevention, early detection, and treatment. Recently, the Research Network reported data derived from 131 muscle-invasive, chemotherapy-naiv̈ e urothelial bladder carcinoma tumors ((2014) Nature, 507, 315−322). DNA copy numbers, somatic mutations, mRNA and microRNA expression, DNA methylation, and histopathology were just some of the data sets acquired in the study. Genome sequencing revealed that the tumors had, on average, 302 exonic mutations, 204 segmental alterations in copy number, and 22 genomic arrangements per sample. A number of genes were identified that had never been previously associated with bladder cancers, including CDKN1A, which encodes a cyclin-dependent kinase inhibitor, and ERCC2, which encodes a nucleotide excision repair protein. Furthermore, the team identified potential pathways for therapeutic targeting, including chromatin remodeling, for which genes were mutated in 76% of the tumors examined in the study, which is the highest proportion among any of the other common cancers studied by TCGA so far. Heidi A. Dahlmann © 2014 American Chemical Society
AGMATINE CONSUMPTION INFLUENCES METABOLISM
For people struggling with the negative health consequences of obesity, it may be advantageous to develop a drug that would induce effects like those brought on by calorie restriction. To this end, the endogenous small molecule, agmatine, has potential for therapeutic application. Agmatine, which is formed by the decarboxylation of arginine in the mammalian brain, is known to modulate neuronal activity, to promote mitochondrial function, and to confer protection from energy stress, among other physiological and metabolic effects. How it performs these functions and how it impacts whole-body metabolism and gene expression were recently investigated by Itzhak Nissim and co-workers ((2014) J. Biol. Chem., 289, 9710− 9729). The research team determined gene expression changes and assessed metabolic fluxes in rats supplemented with agmatine for 4 or 8 weeks. They found that rats treated with agmatine had increased synthesis and tissue levels of cyclic adenosine monophosphate (cAMP). Consequently, the expression of genes associated with thermogenesis, gluconeogenesis, and carnitine biosynthesis and transport was upregulated. The downstream effects of these changes in gene expression included reduced weight gain and diminished hormonal and metabolic derangements associated with high-fat-diet-induced obesity. The authors note that the exact mechanism by which agmatine induces an increase in cAMP is still unknown, and they caution that longterm studies are needed to assess the safety of manipulating metabolism through agmatine consumption. Heidi A. Dahlmann Published: May 19, 2014 711
dx.doi.org/10.1021/tx5001442 | Chem. Res. Toxicol. 2014, 27, 711−712
Chemical Research in Toxicology
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Spotlight
FOOD-DERIVED GLYCOTOXINS INDUCE COGNITIVE DECLINE AND INSULIN RESISTANCE
conjugation with target electrophilic and free radical species in the cell. In the human body, abnormal levels of glutathione can reflect disease status or excessive exposure to xenobiotics. Depending on the detection method, measuring glutathione in a biological sample can be complicated by the need to distinguish between GSH, GSSG, and other intracellular thiols such as cysteine (Cys) and homocysteine (Hcy). In response to this challenge, a research team led by Ji-Hwan Ryu and Juyoung Yoon has developed a fluorescent probe that can be used to image glutathione selectively under physiological conditions ((2014) J. Am. Chem. Soc., 136, 5351−5358). Their cyanine-based sulfonamide probe (2) is preferentially cleaved by GSH rather than by Cys and Hcy to produce a fluorescent signal that can be visualized in cells and tissue samples. Modeling studies indicated that the selectivity of probe 2 for GSH may stem from a combination of steric accessibility and hydrogen-bonding contacts. The authors, who used the probe to demonstrate glutathione depletion in living mice treated with the thiol-reactive reagent, N-methylmaleimide, propose that probe 2 will be a functional tool for GSH detection in future animal studies. Heidi A. Dahlmann
Few people would resist indulging in golden french fries or bread fresh from the oven. However, the very molecules that give fried and baked foods their attractive colors and odors can contribute to the development of metabolic, vascular, and cognitive disorders. During heating, sugar molecules react with amino acids in a process caused glycation; further chemical transformations result in advanced glycation end products (AGEs). In the body, AGEs bind with a protein called Receptor for Advanced Glycation End products (RAGE), which activates a downstream pathway, leading to inflammation. Furthermore, AGEs bind with AGER1, a receptor that suppresses levels of SIRT1, a protein implicated in insulin receptor signaling and cognitive function. The mechanism by which AGEs contribute to pathogenesis has been further explored recently by a research team led by Helen Vlassara ((2014) PNAS, 111, 4940−4945). In the study, mice were fed isocaloric diets consisting either of normal chow or chow in which a particular type of AGE, methyl-glyoxal derivatives (MG), was reduced or increased. The brains of mice supplemented with low-MG diets had higher levels of SIRT1 and lower levels of Aβ, the main component of amyloid plaques that accumulate in the brains of Alzheimer’s disease patients. Conversely, mice fed higher levels of MG displayed cognitive and motor defects as well as biochemical signatures of oxidative stress and insulin resistance. The authors found that the effects in mice were paralleled in older human subjects, in whom oral AGE intake correlated with elevated serum MG levels and reduced SIRT1 levels as well as evidence of cognitive decline and insulin resistance. Heidi A. Dahlmann
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NEW VIEW OF GLUTATHIONE IN VIVO
Adapted from Yin et al. (2014) J. Am. Chem. Soc., 136, 5351−5358. Copyright 2014 American Chemical Society.
Glutathione, an essential scavenging tripeptide used to maintain intracellular redox homeostasis, is present in cells as an active reduced thiol (GSH), an oxidized dimer (GSSG), or in 712
dx.doi.org/10.1021/tx5001442 | Chem. Res. Toxicol. 2014, 27, 711−712
