Insights into the molecular mechanism of anticancer drug ruxolitinib repurposable in COVID-19 therapy

  1. Manisha Mandal
  2. Shyamapada Mandal

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Abstract

Due to non-availability of specific therapeutics against COVID-19, repurposing of approved drugs is a reasonable option. Cytokines imbalance in COVID-19 resembles cancer; exploration of anti-inflammatory agents, might reduce COVID-19 mortality. The current study investigates the effect of ruxolitinib treatment in SARS-CoV-2 infected alveolar cells compared to the uninfected one from the GSE5147507 dataset. The protein-protein interaction network, biological process and functional enrichment of differentially expressed genes were studied using STRING App of the Cytoscape software and R programming tools. The present study indicated that ruxolitinib treatment elicited similar response equivalent to that of SARS-CoV-2 uninfected situation by inducing defense response in host against virus infection by RLR and NOD like receptor pathways. Further, the effect of ruxolitinib in SARS-CoV-2 infection was mainly caused by significant suppression of IFIH1, IRF7 and MX1 genes as well as inhibition of DDX58/IFIH1-mediated induction of interferon-I and -II signalling.

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  1. ScreenIT

    SciScore for 10.1101/2020.12.29.20248986: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    The gene expression dataset GSE5147507 was obtained from the Gene Expression Omnibus (GEO) database (www.ncbi.nlm.nih.gov/geo/) related to transcriptional response to SARS-CoV-2 infection (Blanco-Melo et al., 2020), from where samples were selected containing independent biological triplicates of (i) transformed lung alveolar (A549) cells transduced with a vector expressing human ACE2 mock treated (GSM4486157: Series16_A549-ACE2_Mock_1, GSM4486158:Series16_A549-ACE2_Mock_2, and GSM4486159:Series16_A549-ACE2_Mock_3), (ii) ACE2 transduced A549 cells with SARS-CoV-2 infection and without ruxolitinib treatment (GSM448616:Series16_A549-ACE2_SARS-CoV-2_1, GSM4486161:Series16_A549-ACE2_SARS-CoV-2_2, and GSM4486162:Series16_A549-ACE2_SARS-CoV-2_3), and (iii) ACE2 transduced A549 cells with SARS-CoV-2 infection and ruxolitinib (500 nM) treatment (GSM4486163:Series16_A549-ACE2_SARS-CoV-2_Rux_1, GSM4486164:Series16_A549-ACE2_SARS-CoV-2_Rux_2, GSM4486165:Series16_A549-ACE2_SARS-CoV-2_Rux_3).
    A549
    suggested: None
    Software and Algorithms
    SentencesResources
    The gene expression dataset GSE5147507 was obtained from the Gene Expression Omnibus (GEO) database (www.ncbi.nlm.nih.gov/geo/) related to transcriptional response to SARS-CoV-2 infection (Blanco-Melo et al., 2020), from where samples were selected containing independent biological triplicates of (i) transformed lung alveolar (A549) cells transduced with a vector expressing human ACE2 mock treated (GSM4486157: Series16_A549-ACE2_Mock_1, GSM4486158:Series16_A549-ACE2_Mock_2, and GSM4486159:Series16_A549-ACE2_Mock_3), (ii) ACE2 transduced A549 cells with SARS-CoV-2 infection and without ruxolitinib treatment (GSM448616:Series16_A549-ACE2_SARS-CoV-2_1, GSM4486161:Series16_A549-ACE2_SARS-CoV-2_2, and GSM4486162:Series16_A549-ACE2_SARS-CoV-2_3), and (iii) ACE2 transduced A549 cells with SARS-CoV-2 infection and ruxolitinib (500 nM) treatment (GSM4486163:Series16_A549-ACE2_SARS-CoV-2_Rux_1, GSM4486164:Series16_A549-ACE2_SARS-CoV-2_Rux_2, GSM4486165:Series16_A549-ACE2_SARS-CoV-2_Rux_3).
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    The PPI network was constructed with the DEGs using STRING App of the Cytoscape software, version 3.7.2 (https://cytoscape.org/), as per Shannon et al. (2003).
    STRING
    suggested: (STRING, RRID:SCR_005223)
    The DEGs |log10FC| were analysed at the functional level for GeneOntology (GO) and functional pathway enrichment using the STRING Enrichment App of Cytoscape, with p value<0.05 as the cut-off criterion.
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04348071Not yet recruitingSafety and Efficacy of Ruxolitinib for COVID-19
    NCT04334044RecruitingTreatment of SARS Caused by COVID-19 With Ruxolitinib

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.12.29.20248986v1 on medRxiv