scholarly journals Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

2021 ◽  
Vol 11 ◽  
Author(s):  
Wanyan Wang ◽  
Jiayan Cui ◽  
Hui Ma ◽  
Weiqiang Lu ◽  
Jin Huang
Keyword(s):  
Cancer Progression ◽  
Living Organism ◽  
Precision Oncology ◽  
Dihydroorotate Dehydrogenase ◽  
Pyrimidine Metabolism ◽  
Oncogenic Signaling ◽  
Pyrimidine Synthesis ◽  
Dna And Rna ◽  
Rna Biosynthesis ◽  
Survival And Growth

Metabolic rewiring is considered as a primary feature of cancer. Malignant cells reprogram metabolism pathway in response to various intrinsic and extrinsic drawback to fuel cell survival and growth. Among the complex metabolic pathways, pyrimidine biosynthesis is conserved in all living organism and is necessary to maintain cellular fundamental function (i.e. DNA and RNA biosynthesis). A wealth of evidence has demonstrated that dysfunction of pyrimidine metabolism is closely related to cancer progression and numerous drugs targeting pyrimidine metabolism have been approved for multiple types of cancer. However, the non-negligible side effects and limited efficacy warrants a better strategy for negating pyrimidine metabolism in cancer. In recent years, increased studies have evidenced the interplay of oncogenic signaling and pyrimidine synthesis in tumorigenesis. Here, we review the recent conceptual advances on pyrimidine metabolism, especially dihydroorotate dehydrogenase (DHODH), in the framework of precision oncology medicine and prospect how this would guide the development of new drug precisely targeting the pyrimidine metabolism in cancer.

scholarly journals Integration of metabolomics and transcriptomics indicates changes in MRSA exposed to terpinen-4-ol

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Feng Cheng ◽  
Yanan Mo ◽  
Keyuan Chen ◽  
Xiaofei Shang ◽  
Zhen Yang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Dna Synthesis ◽  
Metabolic Pathways ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Pyrimidine Metabolism ◽  
Dna And Rna ◽  
Good Antibacterial Activity ◽  
Rna Biosynthesis ◽  
Differential Genes

Abstract Background This study investigated the effects of terpinen-4-ol on methicillin-resistant Staphylococcus aureus (MRSA) and its biofilm, and the possible mechanisms governing this effect. Results We observed that terpinen-4-ol has good antibacterial activity and inhibits the formation of MRSA biofilm. The MIC and MBC values for terpinen-4-ol against S. aureus were 0.08% ~ 0.32%. And terpinen-4-ol at 0.32% could kill all bacteria and clear all biofilms. Untargeted metabolomic and transcriptomic analyses showed that terpinen-4-ol strongly inhibited DNA and RNA biosynthesis in MRSA at 2 h after treatment by affecting genes and metabolites related to purine and pyrimidine metabolic pathways. Some differential genes which play important roles in DNA synthesis and the production of eDNA from biofilm exposed to terpinen-4-ol was also significantly decreased compared with that of the control. Conclusions Terpinen-4-ol has good antibacterial activity and significantly inhibits the formation of MRSA biofilm by inhibiting purine and pyrimidine metabolism.

scholarly journals Integration of Metabolomics and Transcriptomics Indicates Changes in MRSA Exposed to Terpinen-4-ol

2021 ◽  
Author(s):  
Feng Cheng ◽  
Yanan Mo ◽  
Keyuan Chen ◽  
Xiaofei Shang ◽  
Zhen Yang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Dna Synthesis ◽  
Metabolic Pathways ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Pyrimidine Metabolism ◽  
Dna And Rna ◽  
Good Antibacterial Activity ◽  
Rna Biosynthesis ◽  
Differential Genes

Abstract Background: This study investigated the effects of terpinen-4-ol on methicillin-resistant Staphylococcus aureus (MRSA) and its biofilm, and the possible mechanisms governing this effect.Results: We observed that terpinen-4-ol has good antibacterial activity and inhibits the formation of MRSA biofilm. The MIC and MBC values for terpinen-4-ol against S. aureus were 0.08%~0.32%. And terpinen-4-ol at 0.32% could kill all bacteria and clear all biofilms. Untargeted metabolomic and transcriptomic analyses showed that terpinen-4-ol strongly inhibited DNA and RNA biosynthesis in MRSA at 2 h after treatment by affecting genes and metabolites related to purine and pyrimidine metabolic pathways. Some differential genes which play important roles in DNA synthesis and the production of eDNA from biofilm exposed to terpinen-4-ol was also significantly decreased compared with that of the control. Conclusions: Terpinen-4-ol has good antibacterial activity and significantly inhibits the formation of MRSA biofilm by inhibiting purine and pyrimidine metabolism.

scholarly journals Current status of ctDNA in precision oncology for hepatocellular carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yan Li ◽  
Yuanyuan Zheng ◽  
Liwei Wu ◽  
Jingjing Li ◽  
Jie Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Diagnostic Technique ◽  
Response Assessment ◽  
Selection Response ◽  
Circulating Tumor Dna ◽  
Current Status ◽  
Precision Oncology ◽  
Tumor Biopsy ◽  
Non Invasive

AbstractThe conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.

scholarly journals Targeting CD82/KAI1 for Precision Therapeutics in Surmounting Metastatic Potential in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4486
Author(s):  
Maximillian Viera ◽  
George Wai Cheong Yip ◽  
Han-Ming Shen ◽  
Gyeong Hun Baeg ◽  
Boon Huat Bay
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Therapeutic Approach ◽  
Traditional Approach ◽  
Unmet Need ◽  
Great Promise ◽  
Metastasis Suppressor ◽  
Precision Oncology ◽  
Breast Cancer Patients

Metastasis is the main cause of mortality in breast cancer patients. There is an unmet need to develop therapies that can impede metastatic spread. Precision oncology has shown great promise for the treatment of cancers, as the therapeutic approach is tailored to a specific group of patients who are likely to benefit from the treatment, rather than the traditional approach of “one size fits all”. CD82, also known as KAI1, a glycoprotein belonging to the tetraspanin family and an established metastasis suppressor, could potentially be exploited to hinder metastases in breast cancer. This review explores the prospect of targeting CD82 as an innovative therapeutic approach in precision medicine for breast cancer patients, with the goal of preventing cancer progression and metastasis. Such an approach would entail the selection of a subset of breast cancer patients with low levels of CD82, and instituting an appropriate treatment scheme tailored towards restoring the levels of CD82 in this group of patients. Proposed precision treatment regimens include current modalities of treating breast cancer, in combination with either clinically approved drugs that could restore the levels of CD82, CD82 peptide mimics or non-coding RNA-based therapeutics.

scholarly journals Zinc Signaling in the Mammary Gland: For Better and for Worse

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1204
Author(s):  
Moumita Chakraborty ◽  
Michal Hershfinkel
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Cancer Progression ◽  
Cellular Level ◽  
Normal Mammary Gland ◽  
Dna And Rna ◽  
Dna And Rna Synthesis ◽  
Zinc Signaling ◽  
Epithelial Physiology

Zinc (Zn2+) plays an essential role in epithelial physiology. Among its many effects, most prominent is its action to accelerate cell proliferation, thereby modulating wound healing. It also mediates affects in the gastrointestinal system, in the testes, and in secretory organs, including the pancreas, salivary, and prostate glands. On the cellular level, Zn2+ is involved in protein folding, DNA, and RNA synthesis, and in the function of numerous enzymes. In the mammary gland, Zn2+ accumulation in maternal milk is essential for supporting infant growth during the neonatal period. Importantly, Zn2+ signaling also has direct roles in controlling mammary gland development or, alternatively, involution. During breast cancer progression, accumulation or redistribution of Zn2+ occurs in the mammary gland, with aberrant Zn2+ signaling observed in the malignant cells. Here, we review the current understanding of the role of in Zn2+ the mammary gland, and the proteins controlling cellular Zn2+ homeostasis and signaling, including Zn2+ transporters and the Gq-coupled Zn2+ sensing receptor, ZnR/GPR39. Significant advances in our understanding of Zn2+ signaling in the normal mammary gland as well as in the context of breast cancer provides new avenues for identification of specific targets for breast cancer therapy.

scholarly journals Reactive Oxygen Species: A Key Constituent in Cancer Survival

2018 ◽  
Vol 13 ◽  
pp. 117727191875539 ◽  
Author(s):  
Seema Kumari ◽  
Anil Kumar Badana ◽  
Murali Mohan G ◽  
Shailender G ◽  
RamaRao Malla
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Progression ◽  
Cancer Survival ◽  
Reactive Oxygen ◽  
Redox Balance ◽  
High Morbidity ◽  
Oxygen Species ◽  
Oncogenic Signaling ◽  
Cancer Cell Death ◽  
New Strategy

Background: Cancer is one of the major heterogeneous disease with high morbidity and mortality with poor prognosis. Elevated levels of reactive oxygen species (ROS), alteration in redox balance, and deregulated redox signaling are common hallmarks of cancer progression and resistance to treatment. Mitochondria contribute mainly in the generation of ROS during oxidative phosphorylation. Elevated levels of ROS have been detected in cancers cells due to high metabolic activity, cellular signaling, peroxisomal activity, mitochondrial dysfunction, activation of oncogene, and increased enzymatic activity of oxidases, cyclooxygenases, lipoxygenases, and thymidine phosphorylases. Cells maintain intracellular homeostasis by developing an immense antioxidant system including catalase, superoxide dismutase, and glutathione peroxidase. Besides these enzymes exist an important antioxidant glutathione and transcription factor Nrf2 which contribute in balancing oxidative stress. Reactive oxygen species–mediated signaling pathways activate pro-oncogenic signaling which eases in cancer progression, angiogenesis, and survival. Concomitantly, to maintain ROS homeostasis and evade cancer cell death, an increased level of antioxidant capacity is associated with cancer cells. Conclusions: This review focuses the role of ROS in cancer survival pathways and importance of targeting the ROS signal involved in cancer development, which is a new strategy in cancer treatment.

scholarly journals BIOLOGICAL ACTIVITY OF YERSINIA PSEUDOTUBERCULOSIS TOXINS

2016 ◽  
pp. 10-19
Author(s):  
N. A. Terentieva ◽  
N. F. Timchenko ◽  
V. A. Golotin ◽  
V. A. Rasskazov
Keyword(s):  
Nucleic Acids ◽  
Sea Urchin ◽  
Yersinia Pseudotuberculosis ◽  
Protein Biosynthesis ◽  
Sea Urchin Embryos ◽  
Dna And Rna ◽  
Embryo Cells ◽  
Protein Toxins ◽  
Rna Biosynthesis ◽  
High Concentrations

Aim. Study of effect of heat-labile (HLT) and thermostable (HST) lethal toxins of Yersinia pseudotuberculosis on the development of embryos of sea urchin Strongylocentrotus intermedius, processes of biosynthesis of nucleic acids and protein in embryo cells and activity of nucleoside-kinases of sea urchin. Materials and methods. Y. pseudotuberculosis strains 2517 (pYV-) and 512 (pYV48MD, pYV82MD) were used for isolation of HLT and HST. Gametes and embryos of sea urchin S. intermedius were used to carry out the experiments and isolate nucleoside-kinases. Results. Both of the studied toxins of Y. pseudotuberculosis possessed spermiotoxic effect and reduced fertilizing ability of sea urchin spermies. HLT LD50 was 1 (ig/ml, and HST - 2 pg/ml. Toxins affected the development of embryos of sea urchin resulting in severe morphologic damages, cessation of the development of embryos at early stages of embryogenesis, destruction of cells and death of embryos. Wherein, damaging effect of HLT was observed at lower concentrations compared with HST. HLT inhibited DNA and RNA biosynthesis at concentrations of 1-2 pg/ml. HST did not affect biosynthesis of nucleic acids even at high concentrations, but inhibited protein biosynthesis in sea urchin embryos. HLT did not reduce the level of inclusion of labeled amino acids into embryo cells. HLT had inhibiting effect on the activity of thymidine- and uridine-kinase of sea urchin, whereas HST did not affect these enzymes. Conclusion. Both of Y. pseudotuberculosis protein toxins affect the development of sea urchin embryos, however, mechanisms of action of HLT and HST on embryos and processes occurring in them differ.

scholarly journals Artificial intelligence-aided clinical annotation of a large multi-cancer genomic dataset

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kenneth L. Kehl ◽  
Wenxin Xu ◽  
Alexander Gusev ◽  
Ziad Bakouny ◽  
Toni K. Choueiri ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Language Processing ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Precision Oncology ◽  
Free Survival ◽  
Clinical Endpoints ◽  
Mutation Burden ◽  
Clinical Annotation ◽  
Cancer Types

AbstractTo accelerate cancer research that correlates biomarkers with clinical endpoints, methods are needed to ascertain outcomes from electronic health records at scale. Here, we train deep natural language processing (NLP) models to extract outcomes for participants with any of 7 solid tumors in a precision oncology study. Outcomes are extracted from 305,151 imaging reports for 13,130 patients and 233,517 oncologist notes for 13,511 patients, including patients with 6 additional cancer types. NLP models recapitulate outcome annotation from these documents, including the presence of cancer, progression/worsening, response/improvement, and metastases, with excellent discrimination (AUROC > 0.90). Models generalize to cancers excluded from training and yield outcomes correlated with survival. Among patients receiving checkpoint inhibitors, we confirm that high tumor mutation burden is associated with superior progression-free survival ascertained using NLP. Here, we show that deep NLP can accelerate annotation of molecular cancer datasets with clinically meaningful endpoints to facilitate discovery.

scholarly journals ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia

Haematologica ◽  
2019 ◽  
Vol 105 (9) ◽  
pp. 2286-2297 ◽  
Author(s):  
Jianbiao Zhou ◽  
Jessie Yiying Quah ◽  
Yvonne Ng ◽  
Jing-Yuan Chooi ◽  
Sabrina Hui-Min Toh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Dihydroorotate Dehydrogenase ◽  
Isocitrate Dehydrogenase 1 ◽  
Pyrimidine Synthesis ◽  
Acute Myeloid

Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.

scholarly journals Bombyx mori Dihydroorotate Dehydrogenase: Knockdown Inhibits Cell Growth and Proliferation via Inducing Cell Cycle Arrest

2018 ◽  
Vol 19 (9) ◽  
pp. 2581 ◽  
Author(s):  
Erhu Zhao ◽  
Xiaolan Jiang ◽  
Hongjuan Cui
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Dna Replication ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Bombyx Mori ◽  
Dihydroorotate Dehydrogenase ◽  
Pyrimidine Synthesis ◽  
Cycle Arrest ◽  
Cell Growth And Proliferation

Dihydroorotate dehydrogenase (DHODH), in the de novo pyrimidine biosynthetic pathway, is the fourth enzyme of pyrimidine synthesis and is used to oxidize dihydroorotate and hence to orotat. We cloned and characterized here the dhod of silkworms, Bombyx mori. The full-length cDNA sequence of dhod is 1339 bp, including an open reading frame (ORF) of 1173 bp that encoded a 390 amino acid protein. And two domains were involved in the Dihydroorotate dehydrogenase amino acid sequence of silkworms, Bombyx mori (BmDHODH), namely a DHO_dh domain and a transmembrane domain in N-termina. The silkworm dhod is expressed throughout development and in nine tissues. Moreover, knockdown of the silkworm dhod gene reduced cell growth and proliferation through G2/M phase cell cycle arrest. Similarly, DHODH inhibitor (leflunomide) also reduced cell growth and proliferation, with a significant decrease of cyclin B and cdk2. DHODH is the fourth enzyme of pyrimidine synthesis, so we also found that leflunomide can inhibit, at least in part, the endomitotic DNA replication in silk glands cells. These findings demonstrate that downregulation of BmDHODH inhibits cell growth and proliferation in silkworm cells, and the endomitotic DNA replication in silk gland cells.

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