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https://www.readbyqxmd.com/read/29900057/d-2-hydroxyglutarate-interferes-with-hif-1%C3%AE-stability-skewing-t-cell-metabolism-towards-oxidative-phosphorylation-and-impairing-th17-polarization
#1
Martin Böttcher, Kathrin Renner, Raffaela Berger, Kristin Mentz, Simone Thomas, Zugey Elizabeth Cardenas-Conejo, Katja Dettmer, Peter J Oefner, Andreas Mackensen, Marina Kreutz, Dimitrios Mougiakakos
D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29847930/inhibitors-of-mutant-isocitrate-dehydrogenases-1-and-2-midh1-2-an-update-and-perspective
#2
Tianfang Ma, Fangxia Zou, Stefan Pusch, Yun-Gen Xu, Andreas von Deimling, Xiaoming Zha
Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to -ketoglutarate (-KG) in the tricarboxylic acid cycle. However, mutant IDH1/2 (mIDH1/2) further catalyze -KG to the oncometabolite 2-hydroxyglutarate (2-HG). High levels of 2-HG competitively inhibit the -KG-dependent dioxygenases involved in histone and DNA demethylation, thereby impairing normal cellular differentiation and promoting tumor development. Thus, small molecules that inhibit these mutant enzymes may be therapeutically beneficial...
May 31, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29805076/biological-role-and-therapeutic-potential-of-idh-mutations-in-cancer
#3
REVIEW
Matthew S Waitkus, Bill H Diplas, Hai Yan
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development...
May 14, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29770715/enasidenib-for-the-treatment-of-acute-myeloid-leukemia
#4
James Dugan, Daniel Pollyea
In August 2017 the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2. Areas covered: We review the studies leading to enasidenib's approval, as well as common side effects and safety issues experienced during the clinical trials...
May 17, 2018: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/29769206/targeting-the-idh2-pathway-in-acute-myeloid-leukemia
#5
Maria L Amaya, Daniel A Pollyea
Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. A large percentage of patients succumb to this disease, in spite of aggressive treatments with chemotherapy. Recent advances with mutational analysis led to the discovery of isocitrate dehydrogenase (IDH) mutations in AML. IDH2 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate; its mutated version leads to the accumulation of the oncometabolite (R)-2 hydroxyglutarate, which disrupts several cell processes and leads to a blockage in differentiation...
May 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29753878/targeting-hif-2%C3%AE-as-therapy-for-advanced-cancers
#6
REVIEW
Thanabal Murugesan, Gurukumari Rajajeyabalachandran, Swetha Kumar, Shruthi Nagaraju, Sooriya Kumar
Hypoxia-inducible factors (HIF-1α, -2α -3α, and -β) are key factors that control hypoxia-induced carcinogenic pathways. HIF-1α is predominantly involved in the early stages of cancer, whereas HIF-2α is actively involved in the later stages; in addition, chronic (prolonged) rather than acute (short) hypoxia is a feature of metastasis and chemoresistance that occur during the later stages of cancer. Oncometabolites, onco-miRNAs, glucose deprivation, pseudohypoxia, cytokine/chemokine secretion, and some unique upstream proteins are involved in the signaling switch from HIF-1α to HIF-2α; thus, understanding this signaling switch is critical for the treatment of advanced cancer...
May 10, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29706625/activation-of-ahr-with-nuclear-ikk%C3%AE-regulates-cancer-stem-like-properties-in-the-occurrence-of-radioresistance
#7
Bin Yan, Shuang Liu, Ying Shi, Na Liu, Ling Chen, Xiang Wang, Desheng Xiao, Xiaoli Liu, Chao Mao, Yiqun Jiang, Weiwei Lai, Xing Xin, Can-E Tang, Dixian Luo, Tan Tan, Jiantao Jia, Yating Liu, Rui Yang, Jun Huang, Hu Zhou, Yan Cheng, Ya Cao, Weishi Yu, Kathrin Muegge, Yongguang Tao
Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of 'stemness' genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene...
April 30, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29671246/rapid-detection-of-mutation-in-isocitrate-dehydrogenase-1-and-2-genes-using-mass-spectrometry
#8
Masayuki Kanamori, Masamitsu Maekawa, Ichiyo Shibahara, Ryuta Saito, Masashi Chonan, Miki Shimada, Yukihiko Sonoda, Toshihiro Kumabe, Mika Watanabe, Nariyasu Mano, Teiji Tominaga
The 2016 World Health Organization classification of tumors of the central nervous system was recently revised. Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and chromosome 1p/19q codeletion are especially important for both the integrated diagnosis and the determination of surgical strategy. To establish a method for intraoperative molecular diagnosis, a simple, rapid method was developed for the measurement of 2-hydroxyglutarate (2-HG), a specific oncometabolite formed in the presence of IDH gene mutation, using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS)...
April 2018: Brain Tumor Pathology
https://www.readbyqxmd.com/read/29670690/discovery-of-ag-120-ivosidenib-a-first-in-class-mutant-idh1-inhibitor-for-the-treatment-of-idh1-mutant-cancers
#9
Janeta Popovici-Muller, René M Lemieux, Erin Artin, Jeffrey O Saunders, Francesco G Salituro, Jeremy Travins, Giovanni Cianchetta, Zhenwei Cai, Ding Zhou, Dawei Cui, Ping Chen, Kimberly Straley, Erica Tobin, Fang Wang, Muriel D David, Virginie Penard-Lacronique, Cyril Quivoron, Véronique Saada, Stéphane de Botton, Stefan Gross, Lenny Dang, Hua Yang, Luke Utley, Yue Chen, Hyeryun Kim, Shengfang Jin, Zhiwei Gu, Gui Yao, Zhiyong Luo, Xiaobing Lv, Cheng Fang, Liping Yan, Andrew Olaharski, Lee Silverman, Scott Biller, Shin-San M Su, Katharine Yen
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo...
April 12, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29657328/non-canonical-functions-of-enzymes-facilitate-cross-talk-between-cell-metabolic-and-regulatory-pathways
#10
REVIEW
Marteinn T Snaebjornsson, Almut Schulze
The metabolic rewiring that occurs during cell transformation is a hallmark of cancer. It is diverse in different cancers as it reflects different combinations of oncogenic drivers, tumor suppressors, and the microenvironment. Metabolic rewiring is essential to cancer as it enables uncontrolled proliferation and adaptation to the fluctuating availability of nutrients and oxygen caused by poor access to the vasculature due to tumor growth and a foreign microenvironment encountered during metastasis. Increasing evidence now indicates that the metabolic state in cancer cells also plays a causal role in tumor growth and metastasis, for example through the action of oncometabolites, which modulate cell signaling and epigenetic pathways to promote malignancy...
April 16, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29643764/the-idh1-mutation-induced-oncometabolite-2-hydroxyglutarate-may-affect-dna-methylation-and-expression-of-pd-l1-in-gliomas
#11
Luyan Mu, Yu Long, Changlin Yang, Linchun Jin, Haipeng Tao, Haitao Ge, Yifan E Chang, Aida Karachi, Paul S Kubilis, Gabriel De Leon, Jiping Qi, Elias J Sayour, Duane A Mitchell, Zhiguo Lin, Jianping Huang
Background: Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas. Methods: Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29626092/identification-of-a-metabolic-disposal-route-for-the-oncometabolite-s-2-succino-cysteine-in-bacillus-subtilis
#12
Thomas D Niehaus, Jacob Folz, Donald R McCarty, Arthur J L Cooper, David Moraga Amador, Oliver Fiehn, Andrew D Hanson
Cellular thiols such as cysteine spontaneously and readily react with the respiratory intermediate fumarate, resulting in the formation of stable S -(2-succino)-adducts. Fumarate-mediated succination of thiols increases in certain tumors and in response to glucotoxicity associated with diabetes. Therefore, S -(2-succino)-adducts such as S -(2-succino)cysteine (2SC) are considered oncometabolites and biomarkers for human disease. No disposal routes for S -(2-succino)-compounds have been reported prior to this study...
May 25, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29619216/mutant-idh1-gliomas-downregulate-phosphocholine-and-phosphoethanolamine-synthesis-in-a-2-hydroxyglutarate-dependent-manner
#13
Pavithra Viswanath, Marina Radoul, Jose Luis Izquierdo-Garcia, Hema Artee Luchman, J Gregory Cairncross, Russell O Pieper, Joanna J Phillips, Sabrina M Ronen
Background: Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study was to determine the molecular mechanism underlying this unusual metabolic reprogramming in IDHmut gliomas...
2018: Cancer & Metabolism
https://www.readbyqxmd.com/read/29599405/transketolase-regulates-the-metabolic-switch-to-control-breast-cancer-cell-metastasis-via-the-alpha-ketoglutarate-signaling-pathway
#14
Chien-Wei Tseng, Wen-Hung Kuo, Shih-Hsuan Chan, Hong-Lin Chan, King-Jen Chang, Lu-Hai Wang
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival...
March 29, 2018: Cancer Research
https://www.readbyqxmd.com/read/29594839/o-glcnac-in-cancer-an-oncometabolism-fueled-vicious-cycle
#15
REVIEW
John A Hanover, Weiping Chen, Michelle R Bond
Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes...
March 29, 2018: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/29564224/the-role-of-mitochondrial-h-atp-synthase-in-cancer
#16
REVIEW
Pau B Esparza-Moltó, José M Cuezva
Cancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H+ -ATP synthase-the core hub of oxidative phosphorylation-is downregulated in human carcinomas when compared with its expression in normal tissues. Moreover, some prevalent carcinomas also upregulate the ATPase inhibitory factor 1 (IF1), which is the physiological inhibitor of the H+ -ATP synthase...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29555211/inhibition-of-mtor-complexes-protects-cancer-cells-from-glutamine-starvation-induced-cell-death-by-restoring-akt-stability
#17
Md Wasim Khan, Brian T Layden, Partha Chakrabarti
Glutamine, a well-established oncometabolite, anaplerotically fuels mitochondrial energy metabolism and modulates activity of mammalian/mechanistic target of rapamycin complexes (mTOR). Currently, mTOR inhibitors are in clinical use for certain types of cancer but with limited success. Since glutamine is essential for growth of many cancers, we reasoned that glutamine deprivation under conditions of mTOR inhibition should be more detrimental to cancer cell survival. However, our results show that when cells are deprived of glutamine concomitant with mTOR inhibition, hepatocarcinoma cells elicit an adaptive response which aids in their survival due to enhanced autophagic flux...
June 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29545476/d-2-hydroxyglutarate-is-necessary-and-sufficient-for-isocitrate-dehydrogenase-1-mutant-induced-mir148a-promoter-methylation
#18
Tie Li, Christopher D Cox, Byram H Ozer, Nhung T Nguyen, HuyTram N Nguyen, Thomas J Lai, Sichen Li, Fei Liu, Harley I Kornblum, Linda M Liau, Phioanh L Nghiemphu, Timothy F Cloughesy, Albert Lai
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG-dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP) and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated...
March 15, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29544107/prediction-of-platinum-based-chemotherapy-efficacy-in-lung-cancer-based-on-lc-ms-metabolomics-approach
#19
Feng Peng, Yingzi Liu, Chenjie He, Yi Kong, Qianying Ouyang, Xiaonv Xie, Tong Liu, Zhaoqian Liu, Jingbo Peng
Lung cancer is the common cause of cancer-related death worldwide. Platinum-based chemotherapy is the cornerstone of treatment for lung cancer. Platinum sensitivity is a major possibility for effective cancer treatment. In this study, several potential biomarkers were identified for evaluating and predicting the response to platinum-based chemotherapy. LC-MS-based metabolomics was performed on plasma samples from 43 lung cancer patients with different chemotherapy efficacy. By combing multivariate statistical analysis, pathway analysis with correlation analysis, 8 potential biomarkers were significantly associated with platinum chemotherapy response...
May 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29543066/the-role-of-idh-mutations-in-acute-myeloid-leukemia
#20
Guillermo Montalban-Bravo, Courtney D DiNardo
Isocitrate dehydrogenases (IDHs) are enzymes involved in multiple metabolic and epigenetic cellular processes. Mutations in IDH1 or IDH2 are detected in approximately 20% of patients with acute myeloid leukemia (AML) and induce amino acid changes in conserved residues resulting in neomorphic enzymatic function and production of an oncometabolite, 2-hydroxyglutarate (R-2-HG). This leads to DNA hypermethylation, aberrant gene expression, cell proliferation and abnormal differentiation. IDH mutations diversely affect prognosis of patients with AML based on the location of the mutation and other co-occurring genomic abnormalities...
April 2018: Future Oncology
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