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synthetic lethal

Don Benjamin, Dimitri Robay, Sravanth K Hindupur, Jens Pohlmann, Marco Colombi, Mahmoud Y El-Shemerly, Sauveur-Michel Maira, Christoph Moroni, Heidi A Lane, Michael N Hall
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase...
December 11, 2018: Cell Reports
Fiamma Mantovani, Licio Collavin, Giannino Del Sal
Forty years of research have established that the p53 tumor suppressor provides a major barrier to neoplastic transformation and tumor progression by its unique ability to act as an extremely sensitive collector of stress inputs, and to coordinate a complex framework of diverse effector pathways and processes that protect cellular homeostasis and genome stability. Missense mutations in the TP53 gene are extremely widespread in human cancers and give rise to mutant p53 proteins that lose tumor suppressive activities, and some of which exert trans-dominant repression over the wild-type counterpart...
December 11, 2018: Cell Death and Differentiation
Hideyuki Takahashi, Haruo Watanabe, Kwang Sik Kim, Shigeyuki Yokoyama, Tatsuo Yanagisawa
While Neisseria meningitidis typically exists in an asymptomatic nasopharyngeal carriage state, it may cause potentially lethal diseases in humans, such as septicemia or meningitis, by invading deeper sites in the body. Since the nutrient compositions of human cells are not always conducive to meningococci, N. meningitidis needs to exploit nutrients from host environments. In the present study, the utilization of cysteine by the meningococcal cysteine transport system (CTS) was analyzed for the pathogenesis of meningococcal infections...
December 11, 2018: MBio
Julien Herrou, Jonathan W Willett, Aretha Fiebig, Lydia M Varesio, Daniel M Czyż, Jason X Cheng, Eveline Ultee, Ariane Briegel, Lance Bigelow, Gyorgy Babnigg, Youngchang Kim, Sean Crosson
Molecular components of the Brucella abortus cell envelope play a major role in its ability to infect, colonize and survive inside mammalian host cells. In this study, we have defined a role for a conserved gene of unknown function in B. abortus envelope stress resistance and infection. Expression of this gene, which we name eipA, is directly activated by the essential cell cycle regulator, CtrA. eipA encodes a soluble periplasmic protein that adopts an unusual eight-stranded β-barrel fold. Deletion of eipA attenuates replication and survival in macrophage and mouse infection models, and results in sensitivity to treatments that compromise the cell envelope integrity...
December 8, 2018: Molecular Microbiology
Chao Wang, Gang Wang, Xu Feng, Peter Shepherd, Jie Zhang, Mengfan Tang, Zhen Chen, Mrinal Srivastava, Megan E McLaughlin, Nora M Navone, Glen Traver Hart, Junjie Chen
Ataxia telangiectasia mutated and RAD3 related (ATR) protein kinase plays critical roles in ensuring DNA replication, DNA repair, and cell cycle control in response to replication stress, making ATR inhibition a promising therapeutic strategy for cancer treatment. To identify genes whose loss makes tumor cells hypersensitive to ATR inhibition, we performed CRISPR/Cas9-based whole-genome screens in 3 independent cell lines treated with a highly selective ATR inhibitor, AZD6738. These screens uncovered a comprehensive genome-wide profile of ATR inhibitor sensitivity...
December 7, 2018: Oncogene
Clarence Maikuri Mang'era, Ahmed Hassanali, Fathiya M Khamis, Martin K Rono, Wilber Lwande, Charles Mbogo, Paul O Mireji
Plant-based constituents have been proposed as eco-friendly alternatives to synthetic insecticides for control of mosquito vectors of malaria. In this study, we first screened the effects of methanolic leaf extracts of curry tree (Murraya koenigii) growing in tropical (Mombasa, Malindi) and semi-arid (Kibwezi, and Makindu) ecological zones of Kenya on third instar An. gambiae s.s. larvae. Extracts of the plant from the semi-arid region, and particularly from Kibwezi, led to high mortality of the larvae. Bioassay-guided fractionation of the methanolic extract of the leaves of the plants from Kibwezi was then undertaken and the most active fraction (20 fold more potent than the crude extract) was then analyzed by Liquid chromatography quadruple time of flight coupled with mass spectrometry (LC-QtoF-MS) and a number of constituents were identified, including a major alkaloid constituent, Neplanocin A (5)...
December 7, 2018: Acta Tropica
Eduardo G P Fox, Xiaoqing Wu, Lei Wang, Li Chen, Yong-Yue Lu, Yijuan Xu
Fire ant venom contains insecticidal alkaloids named 'solenopsins'. Whilst species-specific differences are reported, little attention has been given to caste-specific venom adaptations. The venom of fire ant queens has remained particularly poorly studied, though studies have shown it to be strikingly similar across different species, in being primarily composed of the alkaloid isosolenopsin A, regardless of chemical configuration in workers. We predict that this is the evolutionary outcome of stabilising selection, implying that a shared mechanism is responsible for the conserved venom composition among fire ant queens...
December 4, 2018: Toxicon: Official Journal of the International Society on Toxinology
Jacob P Turowec, Esther W T Lau, Xiaowei Wang, Kevin R Brown, Frederic A Fellouse, Kamaldeep K Jawanda, James Pan, Jason Moffat, Sachdev Sidhu
Dysregulation of the ErbB family of receptor tyrosine kinases is involved in the progression of many cancers. Antibodies targeting the dimerization domains of family members EGFR and HER2 are approve cancer therapeutics, but efficacy is restricted to a subset of tumors and resistance often develops in response to treatment. A third family member, HER3, heterodimerizes with both EGFR and HER2 and has also been implicated in cancer. Consequently, there is strong interest in developing antibodies that target HER3, but to date, no therapeutics have been approved...
December 6, 2018: Journal of Biological Chemistry
Nora D Volkow, Emily B Jones, Emily B Einstein, Eric M Wargo
Importance: More than 42 000 Americans died of opioid overdoses in 2016, and the fatalities continue to increase. This review analyzes the factors that triggered the opioid crisis and its further evolution, along with the interventions to manage and prevent opioid use disorder (OUD), which are fundamental for curtailing the opioid crisis. Observations: Opioid drugs are among the most powerful analgesics but also among the most addictive. The current opioid crisis, initially triggered by overprescription of opioid analgesics, which facilitated their diversion and misuse, has now expanded to heroin and illicit synthetic opioids (fentanyl and its analogues), the potency of which further increases their addictiveness and lethality...
December 5, 2018: JAMA Psychiatry
Marta Spochacz, Szymon Chowański, Monika Szymczak, Filomena Lelario, Sabino A Bufo, Zbigniew Adamski
BACKGROUND: Solanaceae plants produce glycoalkaloids (GAs) that affect various physiological processes of herbivorous insects and they are being tested as potential alternatives for synthetic pesticides. They cause lethal and sublethal effects. Nevertheless, their mode of action remains unclear. Therefore, we examined the effects of Solanum nigrum fruit extracts and pure glycoalkaloids on a model beetle, Tenebrio molitor . METHODS: Plant extracts or pure alkaloids were added to the food of the larvae for three days...
December 1, 2018: Toxins
Tai-Yuan Yu, Michael T Kimble, Lorraine S Symington
The Mre11-Rad50-Xrs2NBS1 complex plays important roles in the DNA damage response by activating the Tel1ATM kinase and catalyzing 5'-3' resection at DNA double-strand breaks (DSBs). To initiate resection, Mre11 endonuclease nicks the 5' strands at DSB ends in a reaction stimulated by Sae2CtIP Accordingly, Mre11-nuclease deficient ( mre11-nd ) and sae2Δ mutants are expected to exhibit similar phenotypes; however, we found several notable differences. First, sae2Δ cells exhibit greater sensitivity to genotoxins than mre11-nd cells...
December 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kasey A Hills, Ross V Hyne, Ben J Kefford
Coal mining and extraction of methane from coal beds generate effluent with elevated salinity or major ion concentrations. If discharged to freshwater systems, these effluents may have adverse environmental effects. There is a growing body of work on freshwater invertebrates that indicates variation in the proportion of major ions can be more important than salinity when determining toxicity. However, it is not known if saline toxicity in a subset of species is representative of toxicity across all freshwater invertebrates...
December 3, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Mariana S de Camargo, Rone A De Grandis, Monize M da Silva, Patricia B da Silva, Mariana M Santoni, Carlos E Eismann, Amauri A Menegário, Marcia R Cominetti, Cleslei F Zanelli, Fernando R Pavan, Alzir A Batista
Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: [Ru(pySH)(bipy)(dppb)]PF6 (1), [Ru(HSpym)(bipy)(dppb)]PF6 (2) and Ru[(SpymMe2 )(bipy)(dppb)]PF6 (3) presented anticancer properties higher than doxorubicin and cisplatin and acted as human topoisomerase IB (Topo I) inhibitors. Here, we focused our studies on in vitro intestinal permeability and anticancer mechanisms of these three complexes...
November 30, 2018: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Yufeng Ding, Ni Li, Baijun Dong, Wangxin Guo, Hui Wei, Qilong Chen, Huairui Yuan, Ying Han, Hanwen Chang, Shan Kan, Xuege Wang, Qiang Pan, Ping Wu, Chao Peng, Tong Qiu, Qintong Li, Dong Gao, Wei Xue, Jun Qin
Loss of phosphatase and tensin homolog (PTEN) represents one hallmark of prostate cancer (PCa). However, restoration of PTEN or inhibition of the activated PI3K-AKT pathway has shown limited success, prompting us to identify obligate targets for disease intervention. We hypothesized that PTEN loss might expose cells to unique epigenetic vulnerabilities. Here, we identified a synthetic lethal relationship between PTEN and BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex. Higher BRG1 expression in tumors with low PTEN expression was associated with a worse clinical outcome...
November 29, 2018: Journal of Clinical Investigation
Jianfeng Shen, Wei Zhao, Zhenlin Ju, Lulu Wang, Yang Peng, Marilyne Labrie, Timothy A Yap, Gordon B Mills, Guang Peng
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations...
November 27, 2018: Cancer Research
Tonći Šuštić, Sake van Wageningen, Evert Bosdriesz, Robert J D Reid, John Dittmar, Cor Lieftink, Roderick L Beijersbergen, Lodewyk F A Wessels, Rodney Rothstein, René Bernards
BACKGROUND: Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical trials. Understanding the specific genomic vulnerabilities of KRAS-driven cancers may uncover novel patient-tailored treatment options. METHODS: We first searched for synthetic lethal (SL) genetic interactions with mutant RAS in yeast with the ultimate aim to identify novel cancer-specific targets for therapy...
November 27, 2018: Genome Medicine
Khyati N Shah, Roma Bhatt, Julia Rotow, Julia Rohrberg, Victor Olivas, Victoria E Wang, Golzar Hemmati, Maria M Martins, Ashley Maynard, Jonathan Kuhn, Jacqueline Galeas, Hayley J Donnella, Swati Kaushik, Angel Ku, Sophie Dumont, Gregor Krings, Henry J Haringsma, Liliane Robillard, Andrew D Simmons, Thomas C Harding, Frank McCormick, Andrei Goga, Collin M Blakely, Trever G Bivona, Sourav Bandyopadhyay
Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity...
November 26, 2018: Nature Medicine
Arun M Unni, Bryant Harbourne, Min Hee Oh, Sophia Wild, John R Ferrarone, William W Lockwood, Harold Varmus
Synthetic lethality results when mutant KRAS and EGFR proteins are co-expressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for mutual exclusivity of KRAS and EGFR mutations. We have now defined the biochemical events responsible for the toxic effects by combining pharmacological and genetic approaches and to show that signaling through extracellular signal-regulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes in the RAS pathway must restrain the activity of ERK1/2 to avoid toxicities and enable tumor growth...
November 26, 2018: ELife
Sufang Zhang, Hsiao Hsiang Chao, Xiaoxiao Wang, Zhongtao Zhang, Ernest Y C Lee, Marietta Y W T Lee
Human DNA polymerase δ is normally present in unstressed, non-dividing cells as a heterotetramer (Pol δ4). Its smallest subunit, p12, is transiently degraded in response to UV damage, as well as during the entry into S-phase, resulting in the conversion of Pol δ4 to a trimer (Pol δ3). In order to further understand the specific cellular roles of these two forms of Pol δ, the gene (POLD4) encoding p12 was disrupted by CRISPR/Cas9 to produce p12 knockout (p12KO) cells. Thus, Pol δ4 is absent in p12KO cells, leaving Pol δ3 as the sole source of Pol δ activity...
November 13, 2018: DNA Repair
Diana C Pearre, Krishnansu S Tewari
The last 2 years have ushered in a new era in ovarian cancer therapy with the US Food and Drug Administration's (FDA) approval of poly-ADP ribose polymerase (PARP) inhibitors (PARPi). One of the deadliest cancers that women experience, ovarian cancer, is most often diagnosed in advanced stages. Although cytoreductive surgery and (platinum/taxane-based) chemotherapy can place the majority of patients into remission, most will experience a relapse of their disease in their lifetime. This has led to studies exploring the benefits and efficacy of maintenance treatment...
2018: Therapeutics and Clinical Risk Management
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