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Synthetic lethality

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https://www.readbyqxmd.com/read/28640807/lack-of-a-peroxiredoxin-suppresses-the-lethality-of-cells-devoid-of-electron-donors-by-channelling-electrons-to-oxidized-ribonucleotide-reductase
#1
Susanna Boronat, Alba Domènech, Mercè Carmona, Sarela García-Santamarina, M Carmen Bañó, José Ayté, Elena Hidalgo
The thioredoxin and glutaredoxin pathways are responsible of recycling several enzymes which undergo intramolecular disulfide bond formation as part of their catalytic cycles such as the peroxide scavengers peroxiredoxins or the enzyme ribonucleotide reductase (RNR). RNR, the rate-limiting enzyme of deoxyribonucleotide synthesis, is an essential enzyme relying on these electron flow cascades for recycling. RNR is tightly regulated in a cell cycle-dependent manner at different levels, but little is known about the participation of electron donors in such regulation...
June 22, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28637236/the-ribosome-assembly-gene-network-is-controlled-by-the-feedback-regulation-of-transcription-elongation
#2
Fernando Gómez-Herreros, Thanasis Margaritis, Olga Rodríguez-Galán, Vicent Pelechano, Victoria Begley, Gonzalo Millán-Zambrano, Macarena Morillo-Huesca, Mari Cruz Muñoz-Centeno, José E Pérez-Ortín, Jesús de la Cruz, Frank C P Holstege, Sebastián Chávez
Ribosome assembly requires the concerted expression of hundreds of genes, which are transcribed by all three nuclear RNA polymerases. Transcription elongation involves dynamic interactions between RNA polymerases and chromatin. We performed a synthetic lethal screening in Saccharomyces cerevisiae with a conditional allele of SPT6, which encodes one of the factors that facilitates this process. Some of these synthetic mutants corresponded to factors that facilitate pre-rRNA processing and ribosome biogenesis...
June 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28634224/igh-myc-translocation-associates-with-brca2-deficiency-and-synthetic-lethality-to-parp1-inhibitors
#3
Silvia Maifrede, Kayla Martin, Paulina Podszywalow-Bartnicka, Katherine Sullivan, Samantha K Langer, Reza Nejadi, Yashodhara Dasgupta, Michael Hulse, Daniel Gritsyuk, Margaret Nieborowska-Skorska, Lena N Lupey-Green, Huaqing Zhao, Katarzyna Piwocka, Mariusz A Wasik, Italo Tempera, Tomasz Skorski
Burkitt lymphoma/leukemia (BL) cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive BL cells accumulate a high number of potentially lethal DNA double-strand breaks (DSBs) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro...
June 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28632992/targeting-the-rhogtpase-rock-pathway-for-the-treatment-of-vhl-hif-pathway-driven-cancers
#4
Jordan M Thompson, Jaime Landman, Olga V Razorenova
The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK 1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. As a function of the later effect, we recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation...
June 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/28631432/profile-effects-and-toxicity-of-novel-psychoactive-substances-a-systematic-review-of-quantitative-studies
#5
Sulaf Assi, Nargilya Gulyamova, Kinda Ibrahim, Paul Kneller, David Osselton
OBJECTIVE: To investigate the profile, effects, and toxicity of novel psychoactive substances (NPS). METHODS: A systematic literature review was conducted between May 2015 and February 2016 and included 19 databases. Search terms included "novel psychoactive substance(s)," "effect(s)," and "toxicity" and their synonyms. Studies included were those from any country, in any language, and between January 2007 and April 2015. Studies published before 2007 and those regarding the synthesis of NPS were excluded...
June 19, 2017: Human Psychopharmacology
https://www.readbyqxmd.com/read/28628639/small-molecule-inhibitors-uncover-synthetic-genetic-interactions-of-human-flap-endonuclease-1-fen1-with-dna-damage-response-genes
#6
Thomas A Ward, Peter J McHugh, Stephen T Durant
Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response...
2017: PloS One
https://www.readbyqxmd.com/read/28624672/analysis-of-fire-deaths-in-poland-and-influence-of-smoke-toxicity
#7
Joanna Giebułtowicz, Monika Rużycka, Piotr Wroczyński, David A Purser, Anna A Stec
Dwelling fires have changed over the years because building contents and the materials used in then have changed. They all contribute to an ever-growing diversity of chemical species found in fires, many of them highly toxic. These arise largely from the changing nature of materials in interior finishes and furniture, with an increasing content of synthetic materials containing higher levels of nitrogen, halogen and phosphorus additives. While there is still a belief that carbon monoxide is the major lethal toxic agent in fires, the hydrogen cyanide and acid gases released from these additives are now well-recognised as major contributory causes of incapacitation, morbidity and mortality in domestic fires...
June 9, 2017: Forensic Science International
https://www.readbyqxmd.com/read/28622697/vitamin-c-and-doxycycline-a-synthetic-lethal-combination-therapy-targeting-metabolic-flexibility-in-cancer-stem-cells-cscs
#8
Ernestina Marianna De Francesco, Gloria Bonuccelli, Marcello Maggiolini, Federica Sotgia, Michael P Lisanti
Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility...
June 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28616574/therapeutic-arginine-starvation-in-ass1-deficient-cancers-inhibits-the-warburg-effect
#9
Jeff C Kremer, Brian A Van Tine
Argininosuccinate Synthetase 1 deficiency induces dependence on extracellular arginine for continued cellular growth and survival. Arginine starvation inhibits the Warburg effect and diverts glucose into serine biosynthesis, while simultaneously increasing glutamine metabolism via the tricarboxylic acid cycle. Simultaneous arginine deprivation and inhibition of the subsequent metabolic adaptations induce synthetic lethality.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28602118/effects-of-endocrine-disrupting-chemicals-and-epigenetic-modifications-in-ovarian-cancer-a-review
#10
Ratika Samtani, Noopur Sharma, Deepali Garg
Ovarian cancer (OC) is a relatively fatal female reproductive malignancy. Since the underlying causes are uncertain, it brings us to believe that both genetic and external factors contribute toward development of this lethal disorder. Exposure to endocrine-disrupting chemicals (EDCs) in the form of occupational usage of pesticides, fungicides, herbicides, plasticizers, cosmetics, and so on is potentially carcinogenic and their ability to cause epigenetic modifications has led us to hypothesize that they may play a catalytic role in OC progression...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/28598559/new-structural-classes-of-antituberculosis-agents
#11
REVIEW
Vajinder Kumar, Sanjay Patel, Rahul Jain
Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB...
June 9, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28587915/acrylfentanyl-another-new-psychoactive-drug-with-fatal-consequences
#12
Davide Guerrieri, Emma Rapp, Markus Roman, Gunilla Thelander, Robert Kronstrand
The European Nordic Countries are the most exposed to opioid-related deaths. Between April and October 2016, a series of forty lethal intoxications occurred in Sweden, in which the presence of the synthetic opioid acrylfentanyl was determined to be the main - or a contributing - cause of death. In the reported cases, the blood concentration of acrylfentanyl - mostly detected in combination with other drugs - ranged from 0.01ng/g to 5ng/g; victims were predominantly males (34 males and 6 females), and their age varied between 18 and 53 years...
May 22, 2017: Forensic Science International
https://www.readbyqxmd.com/read/28586114/a-phosphokinome-based-screen-uncovers-new-drug-synergies-for-cancer-driven-by-liver-specific-gain-of-non-oncogenic-rtks
#13
Yannan Fan, Maria Arechederra, Sylvie Richelme, Fabrice Daian, Chiara Novello, Julien Calderaro, Luca Di Tommaso, Guillaume Morcrette, Sandra Rebouissou, Matteo Donadon, Emanuela Morenghi, Jessica Zucman-Rossi, Massimo Roncalli, Rosanna Dono, Flavio Maina
Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis; however, the cellular vulnerability to non-oncogenic RTK fluctuations has not been characterized. Here, we demonstrated genetically that liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26(Met) ), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage...
June 6, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28584133/mitochondrial-dysfunction-induced-by-a-sh2-domain-targeting-stat3-inhibitor-leads-to-metabolic-synthetic-lethality-in-cancer-cells
#14
Davide Genini, Lara Brambilla, Erik Laurini, Jessica Merulla, Gianluca Civenni, Shusil Pandit, Rocco D'Antuono, Laurent Perez, David E Levy, Sabrina Pricl, Giuseppina M Carbone, Carlo V Catapano
In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28583748/development-of-parp-inhibitors-in-gynecological-malignancies
#15
REVIEW
Yvonne L E Ang, David S P Tan
PARP inhibitors demonstrate synthetic lethality in tumors with BRCA1/2 mutations and other homologous recombination repair deficiencies by interfering with DNA repair and causing direct toxicity to DNA through PARP trapping. PARP inhibitors have been shown to be beneficial in the treatment of BRCA1/2-mutated ovarian cancers, which has led to a shift in the treatment paradigm of this disease. Further studies to establish the role of PARP inhibitors during earlier stages of treatment are ongoing. The use of PARP inhibitors in other cancers with homologous recombination repair deficiencies, such as breast cancer and prostate cancer, is gradually evolving as well, including their use in the neoadjuvant and adjuvant settings...
March 14, 2017: Current Problems in Cancer
https://www.readbyqxmd.com/read/28578026/%C3%AE-pyrrolidinononanophenone-provokes-apoptosis-of-neuronal-cells-through-alterations-in-antioxidant-properties
#16
Toshiyuki Matsunaga, Yoshifumi Morikawa, Kyohei Kamata, Akinobu Shibata, Hidetoshi Miyazono, Yasuhide Sasajima, Koichi Suenami, Kiyohito Sato, Yuji Takekoshi, Satoshi Endo, Ossama El-Kabbani, Akira Ikari
In this study, we found that exposure to α-pyrrolidinononanophenone (α-PNP), a highly lipophilic synthetic cathinone, provokes apoptosis of human neuronal SK-N-SH cells. The drug sensitivity of the cells (50% lethal concentration of 12μM) was similar to those of aortic endothelial and smooth muscle cells, and was higher than those of cells derived from colon, liver, lung and kidney, suggesting that α-PNP overdose and abuse cause serious damage in central nervous and vascular systems. SK-N-SH cell treatment with lethal concentrations (20 and 50μM) of α-PNP facilitated the reactive oxygen species (ROS) production...
May 31, 2017: Toxicology
https://www.readbyqxmd.com/read/28576570/deinococcus-mn-2-peptide-complex-a-novel-approach-to-alphavirus-vaccine-development
#17
Manoshi Gayen, Paridhi Gupta, Elaine M Morazzani, Elena K Gaidamakova, Barbara Knollmann-Ritschel, Michael J Daly, Pamela J Glass, Radha K Maheshwari
Over the last ten years, Chikungunya virus (CHIKV), an Old World alphavirus has caused numerous outbreaks in Asian and European countries and the Americas, making it an emerging pathogen of great global health importance. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, on the other hand, has been developed as a bioweapon in the past due to its ease of preparation, aerosol dispersion and high lethality in aerosolized form. Currently, there are no FDA approved vaccines against these viruses...
June 22, 2017: Vaccine
https://www.readbyqxmd.com/read/28570035/metabolic-rewiring-in-mutant-kras-lung-cancer
#18
REVIEW
Emma M Kerr, Carla P Martins
Lung cancer is the leading cause of cancer related death worldwide, reflecting an unfortunate combination of very high prevalence and low survival rates, as most cases are diagnosed at advanced stages when treatment efficacy is limited. Lung cancer comprises several disease groups with non-small cell lung cancer (NSCLC) accounting for ~85% of cases and lung adenocarcinoma being its most frequent histological subtype. Mutations in KRAS affect ~30% of lung adenocarcinomas but unlike other commonly altered proteins (EGFR and ALK, affected in ~14 and 7% of cases, respectively), mutant KRAS remains untargetable...
June 1, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28569207/seed-effect-modeling-improves-the-consistency-of-genome-wide-loss-of-function-screens-and-identifies-synthetic-lethal-vulnerabilities-in-cancer-cells
#19
Alok Jaiswal, Gopal Peddinti, Yevhen Akimov, Krister Wennerberg, Sergey Kuznetsov, Jing Tang, Tero Aittokallio
BACKGROUND: Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off-target effects. Currently, a detailed understanding of the key factors contributing to the sub-optimal consistency is still a lacking, especially on how to improve the reliability of future RNAi screens by controlling for factors that determine their off-target propensity...
June 1, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28567486/xenobiology-state-of-the-art-ethics-and-philosophy-of-new-to-nature-organisms
#20
Markus Schmidt, Lei Pei, Nediljko Budisa
The basic chemical constitution of all living organisms in the context of carbon-based chemistry consists of a limited number of small molecules and polymers. Until the twenty-first century, biology was mainly an analytical science and has now reached a point where it merges with engineering science, paving the way for synthetic biology. One of the objectives of synthetic biology is to try to change the chemical compositions of living cells, that is, to create an artificial biological diversity, which in turn fosters a new sub-field of synthetic biology, xenobiology...
June 1, 2017: Advances in Biochemical Engineering/biotechnology
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