Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2

Antar, Samar A.; Saleh, Mohamed A.; Al‐Karmalawy, Ahmed A.

doi:10.1016/j.lfs.2022.121048

Cited by 29 publications

(23 citation statements)

References 153 publications

(154 reference statements)

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“…PFD (200 mg/kg once every other day) and cisplatin (5 mg/kg twice per week) were administered by intraperitoneal injection for 4 weeks, and the mice were sacrificed 3 days after the last treatment with PFD and cisplatin. The drug dosage used in the in vivo experiments was determined based on the reference source 34 . Mice in the remaining groups were injected with 4 × 10 6 A549 or H1299 cells pretreated with PFD without any other drug intervention.…”

Section: Resultsmentioning

confidence: 99%

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Pirfenidone inhibits TGF‐β1‐induced metabolic reprogramming during epithelial‐mesenchymal transition in non‐small cell lung cancer

Zhang,

Wang,

Luo

et al. 2023

J Cellular Molecular Medi

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Metastasis is an important contributor to increased mortality rates in non‐small cell lung cancer (NSCLC). The TGF‐β signalling pathway plays a crucial role in facilitating tumour metastasis through epithelial‐mesenchymal transition (EMT). Glycolysis, a key metabolic process, is strongly correlated with NSCLC metastasis. Pirfenidone (PFD) has been shown to safely and effectively inhibit TGF‐β1 in patients with lung diseases. Furthermore, TGF‐β1 and glycolysis demonstrate an interdependent relationship within the tumour microenvironment. Our previous study demonstrated that PFD effectively inhibited glycolysis in NSCLC cells, prompting further investigation into its potential antitumour effects in this context. Therefore, the present study aims to investigate the potential antitumour effect of PFD in NSCLC and explore the relationship among TGF‐β1, glycolysis and EMT through further experimentation. The antitumour effects of PFD were evaluated using five different NSCLC cell lines and a xenograft tumour model. Notably, PFD demonstrated a significant antitumour effect specifically in highly glycolytic H1299 cells. To elucidate the underlying mechanism, we compared the efficacy of PFD after pretreatment with either TGF‐β1 or a TGF‐β receptor inhibitor (LY2109761). The energy metabolomics analysis of tumour tissue demonstrated that PFD, a chemosensitizing agent, reduced lactate and ATP production, thereby inhibiting glycolysis and exerting synergistic antineoplastic effects. Additionally, PFD combined with cisplatin targeted TGF‐β1 to inhibit glycolysis during EMT and enhanced the chemosensitization of A549 and H1299 cells. The magnitude of the anticancer effect exhibited by PFD was intricately linked to its metabolic properties.

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Section: Resultsmentioning

confidence: 99%

“…The drug dosage used in the in vivo experiments was determined based on the reference source. 34 Mice in the remaining groups were injected with…”

Section: Pfd Synergizes With Cisplatin To Exert An Antitumour Effect ...mentioning

confidence: 99%

Pirfenidone inhibits TGF‐β1‐induced metabolic reprogramming during epithelial‐mesenchymal transition in non‐small cell lung cancer

Zhang,

Wang,

Luo

et al. 2023

J Cellular Molecular Medi

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“…Pirfenidone ( 38 , Figure ), a small molecule commonly in use for the treatment of idiopathic pulmonary fibrosis (IPF), has also previously been used in combination with azithromycin and prednisolone in treating patients with post-H1N1 ARDS pulmonary fibrosis. Pirfenidone has demonstrated anti-inflammatory, antioxidant, and anti-fibrotic properties in several studies previously while also showing efficacy in treating pro-fibrotic alterations and inflammatory dysregulation brought in by the SARS-CoV-2 infection …”

Section: Lipid-inspired Therapeutics For Covid-19mentioning

confidence: 99%

“…Pirfenidone has demonstrated anti-inflammatory, antioxidant, and anti-fibrotic properties in several studies previously while also showing efficacy in treating pro- fibrotic alterations and inflammatory dysregulation brought in by the SARS-CoV-2 infection. 143 The ability of other oral or inhaled corticosteroids to improve COVID-19-related pathology warrants further exploration. Serum levels of arachidonate-derived pro-inflammatory lipid mediators, such as prostaglandins, are critical for COVID-19 pathology, and overexpression of pro-resolving mediators (e.g., resolvin E3) is a characteristic of moderately ill COVID-19 patients.…”

Section: Controlling the Cytokine Storm And Inflammatorymentioning

confidence: 99%

Mapping the Lipid Signatures in COVID-19 Infection: Diagnostic and Therapeutic Solutions

Dasgupta,

Gangai,

Narayan

et al. 2023

J. Med. Chem.

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The COVID-19 pandemic ignited research centered around the identification of robust biomarkers and therapeutic targets. SARS-CoV-2, the virus responsible, hijacks the metabolic machinery of the host cells. It relies on lipids and lipoproteins of host cells for entry, trafficking, immune evasion, viral replication, and exocytosis. The infection causes host cell lipid metabolic remodelling. Targeting lipid-based processes is thus a promising strategy for countering COVID-19. Here, we review the role of lipids in the different steps of the SARS-CoV-2 pathogenesis and identify lipid-centric targetable avenues. We discuss lipidome changes in infected patients and their relevance as potential clinical diagnostic or prognostic biomarkers. We summarize the emerging direct and indirect therapeutic approaches for targeting COVID-19 using lipid-inspired approaches. Given that viral protein-targeted therapies may become less effective due to mutations in emerging SARS-CoV-2 variants, lipid-inspired interventions may provide additional and perhaps better means of combating this and future pandemics.

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“…Pirfenidone was approved in 2011 by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a first-line therapy for varying-severity Idiopathic Pulmonary Fibrosis (IPF) [ 19 ]. The different effects of pirfenidone are based on several mechanisms, as it can inhibit apoptosis, and regulate tumor necrosis factor-alpha (TNF-α) and -beta secretions, transforming growth factor-5 (TGF-5) activity, and cellular oxidation [ 20 ]. Taking into account these mechanisms and the well-investigated pathophysiology associated with COVID-19 infection, it seems logical to anticipate that pirfenidone and other antifibrotic therapies could be of value in managing COVID-19-induced lung fibrosis and in protecting pneumocytes and different cells from the invasion of COVID-19 and the cytokine storm [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Pirfenidone on Risk of Pulmonary Fibrosis in COVID-19 Patients Experiencing Cytokine Storm

Boshra

Warda

Sayed³

et al. 2022

Healthcare

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Objectives: Severe stages of COVID-19 infection have been associated with the excessive discharge of pro-inflammatory mediators such as cytokines, resulting in lung deterioration, which progresses rapidly to lung fibrosis leading to acute respiratory distress syndrome. In this investigation, the efficacy and safety of the novel antifibrotic and anti-inflammatory agent, Pirfenidone, were assessed in COVID-19 patients with pulmonary fibrosis secondary to cytokine storm. In this randomized controlled study, we assigned 100 adult COVID-19 patients cytokine storm and admitted to the intensive care isolation unit into either pirfenidone added to the standard therapy (n = 47), or the standard protocol only (n = 53). High-resolution computed tomography of the chest was performed in all patients to evaluate fibrotic lesions and their progression. The results showed that the percentage of patients who developed pulmonary fibrosis during cytokine storm onset in the pirfenidone group relative to the standard group was 29.8% and 35.8%, respectively, with no significant difference between the two groups; while there was a significant increase in the proportion of patients discharged from the isolation unit with pulmonary fibrosis without progression in fibrotic lesions in the pirfenidone group compared to the standard group (21.3% and 5.7%, respectively). Furthermore, there was a significant difference concerning liver enzyme elevation and GIT disturbance incidences in the studied groups (p = 0.006 and 0.01, respectively). Our findings show that Pirfenidone inhibits fibrosis advancement in COVID-19 patients with pulmonary fibrosis and is associated with hepatotoxicity and GI distress. It may be beneficial in patients with mild to moderate COVID-19-induced pulmonary fibrosis; however, additional research is necessary.

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Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2

Cited by 29 publications

References 153 publications

Pirfenidone inhibits TGF‐β1‐induced metabolic reprogramming during epithelial‐mesenchymal transition in non‐small cell lung cancer

Pirfenidone inhibits TGF‐β1‐induced metabolic reprogramming during epithelial‐mesenchymal transition in non‐small cell lung cancer

Mapping the Lipid Signatures in COVID-19 Infection: Diagnostic and Therapeutic Solutions

Effect of Pirfenidone on Risk of Pulmonary Fibrosis in COVID-19 Patients Experiencing Cytokine Storm

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