Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling

AbstractSmoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.

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Computer-aided prediction of inhibitors against STAT3 for managing COVID-19 associate cytokine storm

10.21203/rs.3.rs-495671/v1 ◽

2021 ◽

Author(s):

Anjali Dhall ◽

Sumeet Patiyal ◽

Neelam Sharma ◽

Naorem Leimarembi Devi ◽

Gajendra P. S. Raghava

Keyword(s):

Prediction Models ◽

Validation Dataset ◽

Cytokine Storm ◽

Hybrid Features ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Wide Range ◽

Proinflammatory Responses ◽

Highly Correlated ◽

Approved Drugs

Abstract It has been shown in the past that levels of cytokines, including interleukin 6 (IL6), is highly correlated with the disease severity of COVID-19 patients. IL6 mediated activation of STAT3 is responsible to proliferate proinflammatory responses that leads to promotion of cytokine storm. Thus, STAT3 inhibitors may play a crucial role in managing pathogenesis of COVID-19. This paper describes a method developed for predicting inhibitors against the IL6-mediated STAT3 signaling pathway. The dataset used for training, testing, and evaluation of models contains small-molecule based 1564 STAT3 inhibitors and 1671 non-inhibitors. Analysis of data indicates that rings and aromatic groups are significantly abundant in STAT3 inhibitors compared to non-inhibitors. In order to build models, we generate a wide range of descriptors for each chemical compound. Firstly, we developed models using 2-D and 3-D descriptors and achieved maximum AUC 0.84 and 0.73, respectively. Secondly, fingerprints (FP) are used to build prediction models and achieved 0.86 AUC and accuracy of 78.70% on validation dataset. Finally, models were developed using hybrid features or descriptors, achieve a maximum of 0.87 AUC on the validation dataset. We used our best model to identify STAT3 inhibitors in FDA-approved drugs and found few drugs (e.g., Tamoxifen, and Perindopril) that can be used to manage COVID-19 associated cytokine storm. A webserver “STAT3In” (https://webs.iiitd.edu.in/raghava/stat3in/ ) has been developed to predict and design STAT3 inhibitors.

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The landscape of long noncoding RNA-involved and tumor-specific fusions across various cancers

Nucleic Acids Research ◽

10.1093/nar/gkaa1119 ◽

2020 ◽

Vol 48 (22) ◽

pp. 12618-12631

Author(s):

Mengbiao Guo ◽

Zhen-Dong Xiao ◽

Zhiming Dai ◽

Ling Zhu ◽

Hang Lei ◽

...

Keyword(s):

Cancer Progression ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Chimeric Proteins ◽

Protein Coding ◽

Cellular Processes ◽

Cancer Types ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Somatic Copy Number Alterations

Abstract The majority of the human genome encodes long noncoding RNA (lncRNA) genes, critical regulators of various cellular processes, which largely outnumber protein-coding genes. However, lncRNA-involved fusions have not been surveyed and characterized yet. Here, we present a systematic study of the lncRNA fusion landscape across cancer types and identify >30 000 high-confidence tumor-specific lncRNA fusions (using 8284 tumor and 6946 normal samples). Fusions positively correlated with DNA damage and cancer stemness and were specifically low in microsatellite instable (MSI)-High or virus-infected tumors. Moreover, fusions distribute differently among cancer molecular subtypes, but with shared enrichment in tumors that are microsatellite stable (MSS), with high somatic copy number alterations (SCNA), and with poor survival. Importantly, we find a potentially new mechanism, mediated by enhancer RNAs (eRNA), which generates secondary fusions that form densely connected fusion networks with many fusion hubs targeted by FDA-approved drugs. Finally, we experimentally validate functions of two tumor-promoting chimeric proteins derived from mRNA-lncRNA fusions, KDM4B–G039927 and EPS15L1–lncOR7C2–1. The EPS15L1 fusion protein may regulate (Gasdermin E) GSDME, critical in pyroptosis and anti-tumor immunity. Our study completes the fusion landscape in cancers, sheds light on fusion mechanisms, and enriches lncRNA functions in tumorigenesis and cancer progression.

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Application of the antitussive agents oxelaidin and butamirate as anti-glioma agents

Scientific Reports ◽

10.1038/s41598-021-89238-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sook-Ja Lee ◽

Seon-Yong Yeom ◽

Jee-Young Lee ◽

Chaehwa Park

Keyword(s):

High Throughput Screening ◽

Intraperitoneal Administration ◽

Docking Simulation ◽

Signaling Cascades ◽

Toxic Agents ◽

Ras Family ◽

Cancer Types ◽

Approved Drugs ◽

Antitussive Agents ◽

Fda Approved Drugs

AbstractGlioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM. In this study, high-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on GBM cell lines, LN229, U87 and T98G. Cough suppressants, oxelaidin and butamirate inhibited GBM growth. A Ras family GTPase, Ras-related associated with diabetes (RRAD), contributes to activation of STAT3, which is essential for survival and growth of many cancer types. Interestingly, oxelaidin and butamirate did not affect proliferation in RRAD negative GBM cells. Docking simulation analyses revealed selective interactions between oxelaidin and RRAD. The mechanism by which butamirate and oxelaidin inhibits GBM cell growth involves the suppression of STAT3 transcriptional activity, leading to down-regulation of cyclin D1 and survivin. In addition, components of RRAD-associated signaling cascades, including p-EGFR, p-Akt, and p-STAT3, were inhibited upon oxelaidin treatment. Intraperitoneal administration of oxelaidin or butamirate markedly suppressed tumor growth in a glioblastoma xenograft mouse model without significant adverse effects. Our collective findings indicate that oxelaidin and butamirate exert anti-tumor effects in glioblastoma, supporting its utility as a novel therapeutic candidate for glioblastoma.

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Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

Vaccines ◽

10.3390/vaccines8030401 ◽

2020 ◽

Vol 8 (3) ◽

pp. 401

Author(s):

Chen Peng ◽

Yanan Zhou ◽

Shuai Cao ◽

Anil Pant ◽

Marlene L. Campos Guerrero ◽

...

Keyword(s):

Vaccinia Virus ◽

High Throughput Screening ◽

Janus Kinase ◽

Cellular Functions ◽

Cellular Targets ◽

Stat3 Signaling ◽

Assay Procedure ◽

Stat3 Signaling Pathway ◽

Cellular Pathways ◽

Approved Drugs

Four decades after the eradication of smallpox, poxviruses continue to threaten the health of humans and other animals. Vaccinia virus (VACV) was used as the vaccine that successfully eradicated smallpox and is a prototypic member of the poxvirus family. Many cellular pathways play critical roles in productive poxvirus replication. These pathways provide opportunities to expand the arsenal of poxvirus antiviral development by targeting the cellular functions required for efficient poxvirus replication. In this study, we developed and optimized a secreted Gaussia luciferase-based, simplified assay procedure suitable for high throughput screening. Using this procedure, we screened a customized compound library that contained over 3200 bioactives and FDA (Food and Drug Administration)-approved chemicals, most having known cellular targets, for their inhibitory effects on VACV replication. We identified over 140 compounds that suppressed VACV replication. Many of these hits target cellular pathways previously reported to be required for efficient VACV replication, validating the effectiveness of our screening. Importantly, we also identified hits that target cellular functions with previously unknown roles in the VACV replication cycle. Among those in the latter category, we verified the antiviral role of several compounds targeting the janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3) signaling pathway by showing that STAT3 inhibitors reduced VACV replication. Our findings identify pathways that are candidates for use in the prevention and treatment of poxvirus infections and additionally provide a foundation to investigate diverse cellular pathways for their roles in poxvirus replications.

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Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22136753 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6753

Author(s):

Patrizia Garbati ◽

Raffaella Barbieri ◽

Matilde Calderoni ◽

Francesca Baldini ◽

Mario Nizzari ◽

...

Keyword(s):

Early Childhood ◽

Multidrug Resistance ◽

High Risk ◽

Therapeutic Approaches ◽

Pharmacological Approach ◽

New Therapeutic Approaches ◽

Cancer Types ◽

Approved Drugs ◽

Chemotherapy Efficacy ◽

Fda Approved Drugs

High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.

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