Drug repurposing against COVID-19: focus on anticancer agents

Ciliberto, Gennaro; Mancini, Rita; Paggi, Marco G.

doi:10.1186/s13046-020-01590-2

Cited by 68 publications

(55 citation statements)

References 104 publications

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“…It is particularly noteworthy to mention that part of the most signi cantly predicted pathways targeted by the six microRNAs, were related to respiratory virus infections (e.g., In uenza A) and other viral infections (e.g., Herpes Simplex). The observed microRNA-induced modulation of TMPRSS2 provides new insights for potential assessment of agents capable of regulating the microRNA expression and induces TMPRSS2 downregulation, as SARS-CoV-2 infection prevention strategy [33,34].…”

Section: Discussionmentioning

confidence: 96%

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

Preprint

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Background: SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas.Methods: The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC.Results: TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation.Conclusions: Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

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Section: Discussionmentioning

confidence: 96%

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

Preprint

Self Cite

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“…Several of the other cancer associated genes (GSTA1, ABCG2, CAT, CTSD, TF, EGR1, TNFSF10) appeared in the network (Figure 2c-d) were linked with transcriptional response to SARS-CoV-2 infected cell lines affecting innate immunity (CHRNB4, CAT, CTSD, IFNB1), and endothelial and vascular in ammation (TNF, ICAM) in COVID-19. These DEGs altogether displayed association with old and new drugs potentially useful in COVID-19 therapy and tested or used in the oncological settings as well (Ciliberto et al, 2020), including rapamycin, chloroquine, lopinavir, ritonavir, ribavirin as appeared in PDI network in our study (Figure 6), remdesivir, tocilizumab and sarilumab as shown in virus-human protein interaction (Figure 1). The PDI network of group A genes showed top scores of 0.985 and 0.923 for rapamycin (degree of interaction: 5) with IL10, IL2A, CD8A, CD40LG, and CSF3 (Figure 6a).…”

Section: Resultsmentioning

confidence: 57%

Bioinformatic approaches towards identification of potential repurposable drugs for COVID-19

Mandal

2020

Preprint

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Abstract Repurposing existing drugs approved for other conditions is crucial to identifying specific therapeutics against SARS-CoV-2 causing COVID-19 (coronavirus disease-2019) pandemic. Towards this attempt, it is important to understand how this virus hijacks the host system during the course of infection and determine potential virus- and host-targeted inhibitors. This study elucidates the underlying virus-host interaction based on differentially expressed gene profiling, functional enrichment and pathway analysis, protein-protein and protein-drug interactions utilizing the information on transcriptional response to SARS-CoV-2 infection from GSE 147507 dataset containing COVID-19 case relative to healthy control and infected cell culture compared to uninfected one. Low IFN signaling, chemokines level elevation, and proinflammatory cytokines release were observed markedly. We identified MYC-rapamycin and ABCG2-rapamycin interactions, and unique gene signatures in case (regulation of protein modification and MAPK signaling) as well as in cell (metabolic dysregulation and interferon signaling) different from known COVID-19 genes.

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“…Drug repositioning is a novel attractive strategy used for nding new anticancer agents because it could lower the cost of developing new drugs and introduce them into the market quickly [42,43]. This strategy has also been applied to nd therapeutic agents against coronavirus disease 2019 in the midst of a global emergency when there is no time to conduct phase-III trials [44]. Because HMG-CoA reductase inhibitors have various physiological properties such as regulating metabolisms [45,46], inhibiting in ammation [47,48], modulating the immune system [49], and inhibiting cancer growth [12-14, 50, 51], they are one of the most potent candidate drugs to be used for purposes other than currently approved ones.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin-Romidepsin Combination Kills Bladder Cancer Cells Synergistically

Okubo

Miyai

Kato

et al. 2020

Preprint

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Abstract Background The HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. We postulated that combining simvastatin with the histone deacetylase (HDAC) inhibitor romidepsin would kill bladder cancer cells by inducing histone acetylation cooperatively. Methods Bladder cancer cells (UMUC-3, T-24, J-82, MBT-2) were treated with simvastatin and romidepsin. Cell viability and clonogenicity were assessed by CCK-8 assay and colony formation assay. In-vivo efficacy was evaluated using murine subcutaneous tumor models. Flow cytometry was used to detect annexin-V positive cells and to evaluate cell cycle distribution and cellular reactive oxygen species (ROS) production. Induction of histone acetylation and the expression of AMPK, HDACs, peroxisome proliferator-activated receptor (PPAR) γ, cell-cycle regulators, and the endoplasmic reticulum (ER) stress markers were evaluated by western blotting. Results The combination of romidepsin and simvastatin induced robust apoptosis and killed bladder cancer cells synergistically (combination indexes < 1). It also suppressed colony formation significantly. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment with 0.5 mg/kg romidepsin and 15 mg/kg simvastatin was well tolerated and inhibited tumor growth significantly. Mechanistically, the combination induced histone acetylation by activating AMPK. The combination also decreased the expression of HDACs, thus further promoting histone acetylation. This AMPK activation was essential for the combination’s action because compound C, an AMPK inhibitor, suppressed the combination-induced histone acetylation and the combination’s ability to induce apoptosis. We also found that the combination increased the expression of PPARγ, leading to ROS production. Furthermore, the combination induced ER stress and this ER stress was shown to be associated with increased AMPK expression and histone acetylation, thus playing an important role in the combination’s action. Our study also suggests there is a positive feedback cycle between ER stress induction and PPARγ expression. Conclusions The combination of simvastatin and romidepsin kills bladder cancer cells synergistically. Its mechanism of action includes ER stress induction, AMPK activation, histone acetylation, and increased PPARγ expression. Background There is currently no curative treatment for metastatic bladder cancer and development of novel treatment strategy is urgently needed. AMP-activated protein kinase (AMPK) is a cellular energy sensor, which is activated by impaired energy status such as glucose deprivation, ischemia, hypoxia, and oxidative stress, leading to inhibition of cellular growth to restore energy homeostasis [1]. Therefore, drugs activating AMPK have attracted much attention as novel anticancer agents [2–5]. HMG-CoA reductase inhibitors, which are widely used for treating dyslipidemia [6–9], are known to activate AMPK [10–12]. Simvastatin inhibits HMG-CoA reductase and has been shown to kill cancer cells in vitro [12–14], although its anticancer efficacy has not been proven yet in clinical trials [15].

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Drug repurposing against COVID-19: focus on anticancer agents

Cited by 68 publications

References 104 publications

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Bioinformatic approaches towards identification of potential repurposable drugs for COVID-19

Simvastatin-Romidepsin Combination Kills Bladder Cancer Cells Synergistically

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