Reduced incidence of lung cancer in patients with idiopathic pulmonary fibrosis treated with pirfenidone

Miura, Yukiko; Saito, Takefumi; Tanaka, Toru; Takoi, Hiroyuki; Yatagai, Yohei; Inomata, Minoru; Nei, Takahito; Saito, Yoshinobu; Gemma, Akihiko; Azuma, Arata

doi:10.1016/j.resinv.2017.09.007

Cited by 57 publications

(48 citation statements)

References 30 publications

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“…Interestingly, these growth factor receptors not only participate in IPF, but also in other proliferative diseases such as several malignancies, thus suggesting a protective role of pirfenidone for all of them. Indeed, pirfenidone has demonstrated anti-neoplastic effects in preclinical studies [54], as well as, it has been observed that the incidence of lung cancer in IPF patients treated with pirfenidone is significantly lower than in a non-pirfenidone IPF patient group [55].…”

Section: Figure 3: Pirfenidone (Pfd) Inhibits Muc1-ct Co-localizationmentioning

confidence: 99%

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

2020

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Pirfenidone is a pleiotropic molecule approved to treat idiopathic pulmonary fibrosis (IPF). Pirfenidone has demonstrated to downregulate transforming growth factor-β1 (TGF-β1) cellular effects. However, its anti-fibrotic mechanism remains unclear. Here, we aim to analyze the effects of pirfenidone on the TGF-β1 canonical and non-canonical pathways, as well as, on the most characteristic IPF cellular processes. Results observed in this work showed that TGF-β1-induced canonical SMAD3 and noncanonical ERK1/2 phosphorylations were not inhibited by pirfenidone in alveolar A549 and lung fibroblasts MRC5 cells. In contrast, pirfenidone inhibited TGF-β1-induced MUC1-CT Thr 41 (1224) and Tyr 46 (1229) phosphorylations, thus reducing the β-catenin activation. Additionally, immunoprecipitation and immunofluorescence studies in ATII cells and lung fibroblasts showed that pirfenidone inhibited the formation and nuclear translocation of the transcriptional fibrotic TGF-β1-induced phospho-SMAD3/MUC1-CT/active-β-catenin complex, and consequently the SMAD-binding element activation (SBE). This study provided also evidence of the inhibitory effect of pirfenidone on the TGF-β1-induced ATII to mesenchymal and fibroblast to myofibroblast transitions, fibroblast proliferation and ATII and fibroblast senescence. Therefore, it indicates that pirfenidone's inhibitory effect on TGF-β1-induced fibrotic cellular processes is mediated by the inhibition of MUC1-CT phosphorylation, β-catenin activation, nuclear complex formation of phospho-SMAD3/MUC1-CT/active β-catenin and SBE activation, which may be of value to further develop anti-fibrotic IPF therapies.

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Section: Figure 3: Pirfenidone (Pfd) Inhibits Muc1-ct Co-localizationmentioning

confidence: 99%

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

2020

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“…Antiproliferative effects and antitumor activity of pirfenidone and nintedanib may have a synergistic effect with current chemotherapeutic regimens, but further studies are needed [3,93,94]. A recent study suggests that pirfenidone therapy reduces the incidence of lung cancer [95]. Although there are no reference guidelines, annual lung cancer screening with low-dose CT in high-risk patients with IPF, especially those with CPFE and/or a heavy smoking history, could be considered [65,96].…”

Section: Lung Cancermentioning

confidence: 99%

Comorbidities in idiopathic pulmonary fibrosis: an underestimated issue

et al. 2019

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with a poor prognosis. Between 60% and 70% of IPF patients die of IPF; the remaining causes of death may be due to comorbidities occurring in this ageing population. Interest in the role played by comorbidities in IPF has increased in the past few years. The optimal clinical management of IPF is multifaceted and not only involves antifibrotic treatment, but also vaccinations, oxygen supplementation, evaluation of nutritional status as well as psychological support and patient education. Symptom management, pulmonary rehabilitation, palliative care and treatment of comorbidities represent further areas of clinical intervention. This review analyses the major comorbidities observed in IPF, focusing on those that have the greatest impact on mortality and quality of life (QoL). The identification and treatment of comorbidities may help to improve patients' health-related QoL (i.e. sleep apnoea and depression), while some comorbidities (i.e. lung cancer, cardiovascular diseases and pulmonary hypertension) influence survival. It has been outlined that gathering comorbidities data improves the prediction of survival beyond the clinical and physiological parameters of IPF.

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“…Because TGF-β is a ubiquitous cytokine that is important in normal tissue homeostasis, selective TGF-β inhibition or localized/aerosolized drug delivery methods that target fibrotic fibroblasts may prove useful in combination with mTOR inhibitors [ 250 , 251 , 252 ]. Pirfenidone and nintedanib are both FDA approved for use in IPF with promising safety profiles [ 12 , 253 , 254 , 255 ]. Although the mechanism of action of pirfenidone is not completely understood, the antifibrotic effects are thought to occur indirectly through decreased TGF-β signaling, PI3K/AKT inhibition, and reduced mitochondrial ROS production, and decreased EMT [ 256 , 257 , 258 , 259 ].…”

Section: Therapeutic Targeting Of Mtor In Pulmonary Fibrosismentioning

confidence: 99%

The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis

Lawrence

Nho

2018

IJMS

141

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The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression.

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Reduced incidence of lung cancer in patients with idiopathic pulmonary fibrosis treated with pirfenidone

Cited by 57 publications

References 30 publications

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation

Comorbidities in idiopathic pulmonary fibrosis: an underestimated issue

The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis

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