scholarly journals Integrating multi-omics data reveals function and therapeutic potential of deubiquitinating enzymes

2021 ◽  
Author(s):  
Laura M Doherty ◽  
Caitlin E Mills ◽  
Sarah A Boswell ◽  
Xiaoxi Liu ◽  
Charles Tapley Hoyt ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Turnover ◽  
Therapeutic Potential ◽  
Cancer Cell Line ◽  
Cancer Therapeutics ◽  
Functional Genomic ◽  
Deubiquitinating Enzymes ◽  
Connectivity Map ◽  
Genomic Databases ◽  
Protein Protein Interaction

Deubiquitinating enzymes (DUBs) are proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. Inhibition of DUBs promises to make classically undruggable targets such as the tumor suppressor TP53 and oncogene c-Myc amenable to regulation by small molecules. However, the majority of substrates and pathways regulated by DUBs remain unknown, impeding efforts to prioritize specific enzymes for research and drug development. To assemble a knowledgebase of DUB activities, co-dependent genes, and substrates, we combined targeted experiments using CRISPR libraries and inhibitors with systematic mining of functional genomic databases. Analysis of the Dependency Map, Connectivity Map, Cancer Cell Line Encyclopedia, and protein-protein interaction databases yielded specific hypotheses about DUB function, a subset of which were confirmed in follow-on experiments. The data in this paper, which are browsable online via the DUB Portal, promise to improve understanding of DUBs as a family as well as the activities of specific DUBs such as USP14, UCHL5 and USP7, which have been targeted with investigational cancer therapeutics.

scholarly journals Circular PVT1: an oncogenic non-coding RNA with emerging clinical importance

2019 ◽  
Vol 72 (8) ◽  
pp. 513-519 ◽  
Author(s):  
Jayashree Adhikary ◽  
Sourabrata Chakraborty ◽  
Subhamita Dalal ◽  
Souradip Basu ◽  
Abhijit Dey ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Genetic Locus ◽  
Treatment Protocol ◽  
Clinical Importance ◽  
Cancer Cell Line ◽  
Cancer Therapeutics ◽  
Circular Rnas ◽  
Molecular Alteration ◽  
Primary Tumors ◽  
Non Coding Rna

The importance of circular RNAs (circRNAs) in pathological processes like cancer is evident. Among the circRNAs, recent studies have brought circPVT1 under focus as the most potent oncogenic non-coding RNA. Recent studies on various aspects of circPVT1, including its biogenesis, molecular alteration and its probable role in oncogenesis, have been conducted for research and clinical interest. In this review, a first attempt has been made to summarise the available data on circPVT1 from PubMed and other relevant databases with special emphasis on its role in development, progression and prognosis of various malignant conditions. CircPVT1 is derived from the same genetic locus encoding for long non-coding RNA lncPVT1; however, existing literature suggested circPVT1 and lncPVT1 are transcripted independently by different promoters. The interaction between circRNA and microRNA has been highlighted in majority of the few malignancies in which circPVT1 was studied. Besides its importance in diagnostic and prognostic procedures, circPVT1 seemed to have huge therapeutic potential as evident from differential drug response of cancer cell line as well as primary tumors depending on expression level of the candidate. circPVT1 in cancer therapeutics might be promising as a biomarker to make the existing treatment protocol more effective and also as potential target for designing novel therapeutic intervention.

scholarly journals Phytochemical screening and anticancer activity of the aerial parts extract of Xanthium strumarium L. on HepG2 cancer cell line

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Hai Trieu Ly ◽  
Trieu Minh Truong ◽  
Thi Thu Huong Nguyen ◽  
Hoang Dung Nguyen ◽  
Yuxia Zhao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Proliferative Activity ◽  
Herbal Medicines ◽  
Cancer Cell Line ◽  
Cancer Therapeutics ◽  
Ethanol Extract ◽  
Xanthium Strumarium ◽  
Aerial Parts ◽  
Dual Staining

Abstract Background Cancer is one of the most considerable concerns because of increasing the death rate all over the world. Recent studies have disclosed that plant extracts exhibit anticancer activity through various mechanisms. Xanthium strumarium has been used by Vietnamese in herbal medicines to support the medication of infirmities. This study is to consider the secondary metabolites, antioxidant and anticancer capacities of extract from the aerial parts (stems and leaves) of X. strumarium (AP-XS). Methods AP-XS was analyzed for the presence of phytochemicals via qualitative chemical tests and determined total polyphenol and flavonoid contents. DPPH (1,1-diphenyl-2-picrylhydrazyl) quenching assay and sulforhodamine B (SRB) assay were selected to investigate antioxidant capacity and anti-proliferative activity, respectively. Besides, acridine orange-ethidium bromide (AO-EB) dual staining was applied to evaluate the ability to induce apoptosis on HepG2 cancer cells. Results Results of present study indicated that AP-XS contains the main phytochemicals such as flavonoids, tannins, saponins, alkaloids, and triterpenes. Ethanol extract had highest content of polyphenol (84.86 mg gallic acid equivalent/g dry mass), and exhibited the great total antioxidant property (IC50 = 184.13 μg/mL) and anti-proliferative activity on HepG2 cancer cells (IC50 = 81.69 μg/mL). Furthermore, the characteristics of apoptosis including shrinkage of the cell and apoptotic bodies were found following 60 h of AP-XS extract treatment through AO-EB dual staining. Conclusion The data suggest that AP-XS extract had antioxidant potential and anti-proliferative effect. The anti-proliferative property was considered to have an association with a rising of apoptosis. These results were reliable for further research on X. strumarium as a source of phytochemicals with anticancer activity potential for cancer therapeutics.

scholarly journals Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 851
Author(s):  
Samreen Fathima ◽  
Swati Sinha ◽  
Sainitin Donakonda
Keyword(s):  
Cell Death ◽  
Small Molecules ◽  
Drug Targets ◽  
Apoptotic Cell ◽  
Colon Adenocarcinoma ◽  
Interaction Networks ◽  
Small Cell Lung ◽  
Protein Protein Interaction ◽  
Cell Death Genes ◽  
Death Genes

Programed cell death or apoptosis fails to induce cell death in many recalcitrant cancers. Thus, there is an emerging need to activate the alternate cell death pathways in such cancers. In this study, we analyzed the apoptosis-resistant colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancers transcriptome profiles. We extracted clusters of non-apoptotic cell death genes from each cancer to understand functional networks affected by these genes and their role in the induction of cell death when apoptosis fails. We identified transcription factors regulating cell death genes and protein–protein interaction networks to understand their role in regulating cell death mechanisms. Topological analysis of networks yielded FANCD2 (ferroptosis, negative regulator, down), NCOA4 (ferroptosis, up), IKBKB (alkaliptosis, down), and RHOA (entotic cell death, down) as potential drug targets in colon adenocarcinoma, glioblastoma multiforme, small cell lung cancer phenotypes respectively. We also assessed the miRNA association with the drug targets. We identified tumor growth-related interacting partners based on the pathway information of drug-target interaction networks. The protein–protein interaction binding site between the drug targets and their interacting proteins provided an opportunity to identify small molecules that can modulate the activity of functional cell death interactions in each cancer. Overall, our systematic screening of non-apoptotic cell death-related genes uncovered targets helpful for cancer therapy.

Development of small molecules to target the IgE:FcεRI protein–protein interaction in allergies

2013 ◽  
Vol 5 (12) ◽  
pp. 1423-1435 ◽  
Author(s):  
Lucy D Smith ◽  
Robin J Leatherbarrow ◽  
Alan C Spivey
Keyword(s):  
Small Molecules ◽  
Protein Interaction ◽  
Protein Protein Interaction

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

2020 ◽  
Author(s):  
Chao Wang ◽  
Juan Diez ◽  
Hajeung Park ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Hydroxamic Acid ◽  
Therapeutic Potential ◽  
Preceding Paper ◽  
Close Relative ◽  
Specific Inhibition ◽  
Selective Inhibitors

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

scholarly journals RecQ helicases in DNA repair and cancer targets

2020 ◽  
Vol 64 (5) ◽  
pp. 819-830
Author(s):  
Joseph A. Newman ◽  
Opher Gileadi
Keyword(s):  
Dna Repair ◽  
Small Molecules ◽  
Atp Hydrolysis ◽  
Cancer Therapeutics ◽  
Genome Integrity ◽  
Mechanistic Study ◽  
Synthetic Lethal ◽  
Recq Helicases ◽  
Repair Pathways ◽  
Higher Eukaryotes

Abstract Helicases are enzymes that use the energy derived from ATP hydrolysis to catalyze the unwinding of DNA or RNA. The RecQ family of helicases is conserved through evolution from prokaryotes to higher eukaryotes and plays important roles in various DNA repair pathways, contributing to the maintenance of genome integrity. Despite their roles as general tumor suppressors, there is now considerable interest in exploiting RecQ helicases as synthetic lethal targets for the development of new cancer therapeutics. In this review, we summarize the latest developments in the structural and mechanistic study of RecQ helicases and discuss their roles in various DNA repair pathways. Finally, we consider the potential to exploit RecQ helicases as therapeutic targets and review the recent progress towards the development of small molecules targeting RecQ helicases as cancer therapeutics.

scholarly journals Modulation of PKM activity affects the differentiation of TH17 cells

2020 ◽  
Vol 13 (655) ◽  
pp. eaay9217
Author(s):  
Scott M. Seki ◽  
Kacper Posyniak ◽  
Rebecca McCloud ◽  
Dorian A. Rosen ◽  
Anthony Fernández-Castañeda ◽  
...  
Keyword(s):  
T Cell ◽  
Small Molecules ◽  
Th17 Cells ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Interleukin 17 ◽  
Gm Csf ◽  
T Cell Function ◽  
The Brain ◽  
Tgf Β1

Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of TH17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.

scholarly journals Secondary Metabolites from the Culture of the Marine-derived Fungus Paradendryphiella salina PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 191
Author(s):  
Ambre Dezaire ◽  
Christophe H. Marchand ◽  
Marine Vallet ◽  
Nathalie Ferrand ◽  
Soraya Chaouch ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Crude Extract ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Cancer Cell Line ◽  
Anticancer Activities ◽  
Chemical Library ◽  
Altered Expression ◽  
Cancer Aggressiveness

High-throughput screening assays have been designed to identify compounds capable of inhibiting phenotypes involved in cancer aggressiveness. However, most studies used commercially available chemical libraries. This prompted us to explore natural products isolated from marine-derived fungi as a new source of molecules. In this study, we established a chemical library from 99 strains corresponding to 45 molecular operational taxonomic units and evaluated their anticancer activity against the MCF7 epithelial cancer cell line and its invasive stem cell-like MCF7-Sh-WISP2 counterpart. We identified the marine fungal Paradendryphiella salina PC 362H strain, isolated from the brown alga Pelvetia caniculata (PC), as one of the most promising fungi which produce active compounds. Further chemical and biological characterizations of the culture of the Paradendryphiella salina PC 362H strain identified (-)-hyalodendrin as the active secondary metabolite responsible for the cytotoxic activity of the crude extract. The antitumor activity of (-)-hyalodendrin was not only limited to the MCF7 cell lines, but also prominent on cancer cells with invasive phenotypes including colorectal cancer cells resistant to chemotherapy. Further investigations showed that treatment of MCF7-Sh-WISP2 cells with (-)-hyalodendrin induced changes in the phosphorylation status of p53 and altered expression of HSP60, HSP70 and PRAS40 proteins. Altogether, our study reveals that this uninvestigated marine fungal crude extract possesses a strong therapeutic potential against tumor cells with aggressive phenotypes and confirms that members of the epidithiodioxopiperazines are interesting fungal toxins with anticancer activities.

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