PDE4: A Novel Target in the Treatment of Chronic Obstructive Pulmonary Disease

Michalski, Joel; Golden, Gregory A.; Ikari, Jun; Rennard, Stephen I.

doi:10.1038/clpt.2011.266

Cited by 70 publications

(60 citation statements)

References 75 publications

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“…It has been shown that the enzymatic activity of PDE4 is critical for regulating inflammatory response (8,(10)(11)(12). However, our data revealed that the up-regulated PDE4B2 leads to the induction of certain proinflammatory mediators in a manner that cannot be overcome by high doses of roflumilast (up to 10 μM), a very high level of this drug because the IC 50 has been estimated at less than 1 nM (8).…”

Section: Resultsmentioning

confidence: 46%

“…Recently, roflumilast has been approved as the first PDE4 inhibitor for oral, once-daily treatment of severe COPD with symptoms of chronic bronchitis and a history of exacerbations (12)(13)(14). However, its wide clinical use has been limited by the severe dose-limiting side effects such as emesis and nausea (12,15).…”

mentioning

confidence: 99%

“…PDE4 family, the primary cAMP-specific enzyme, comprises four genes (PDE4A-D), each with multiple variants that encode more than 20 different protein products (8). The therapeutic potential of PDE4 inhibition in airway inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF) has long been explored (9)(10)(11)(12). Recently, roflumilast has been approved as the first PDE4 inhibitor for oral, once-daily treatment of severe COPD with symptoms of chronic bronchitis and a history of exacerbations (12)(13)(14).…”

mentioning

confidence: 99%

“…The therapeutic potential of PDE4 inhibition in airway inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF) has long been explored (9)(10)(11)(12). Recently, roflumilast has been approved as the first PDE4 inhibitor for oral, once-daily treatment of severe COPD with symptoms of chronic bronchitis and a history of exacerbations (12)(13)(14). However, its wide clinical use has been limited by the severe dose-limiting side effects such as emesis and nausea (12,15).…”

mentioning

confidence: 99%

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Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Susuki-Miyata

Miyata

Lee

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit β (PKA-Cβ) and nuclear factor-κB (NF-κB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cβ phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor.PDE4B | Roflumilast | nontypeable Haemophilus influenzae | PKA-Cβ | p65

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Section: Resultsmentioning

confidence: 46%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Susuki-Miyata

Miyata

Lee

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The novel selective phosphodiesterase-4 inhibitors cilomilast and roflumilast inhibit the activation of numerous inflammatory and immune cells in chronic inflammatory diseases. Therefore, their anti-inflammatory effect indicates positive prospects for phosphodiesterase-4 inhibitors in the management of airway mucus hypersecretion (48–50)…”

Section: Novel Types Of Expectorantsmentioning

confidence: 99%

Clinical application of expectorant therapy in chronic inflammatory airway diseases (Review)

Zhang

Zhou

2014

Experimental and Therapeutic Medicine

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Airway mucus hypersecretion is a significant clinical and pathological feature of chronic inflammatory airway diseases. Its clinical presentations include recurrent coughing and phlegm. Airway mucus is closely associated with the occurrence, development and prognosis of chronic inflammatory airway diseases and critically affects the lung function, quality of life, hospitalization rate and mortality of patients with chronic inflammatory airway diseases. Therefore, expectorant therapies targeting the potential mechanisms of mucus hypersecretion have been the focus of numerous studies. Conventional expectorants are mainly mucoactive medicines, including nausea-stimulating expectorants, mucolytics, mucokinetics, and proteases and nucleases. In addition, certain traditional Chinese herbal medicines and non-mucoactive agents, including muscarinic acetylcholine receptor antagonists, corticosteroids, leukotriene receptor antagonists and macrolide antibiotics, have also shown expectorant effects. Several novel medicines for expectorant therapy have emerged, including cholesterol-lowering statins, epidermal growth factor receptor tyrosine kinase inhibitors, phosphodiesterase-4 inhibitors, stanozolol, surfactants, flavonoids, tachykinin receptor antagonists, protease inhibitors, cytokine antagonists and purinergic agonists. With the increasing number of multidisciplinary studies, the effectiveness of expectorant therapy for the treatment of chronic inflammatory airway diseases has been confirmed. Therefore, the development of novel expectorants and the standardization of expectorant therapy are the direction and focus of future studies, thus benefiting patients who have a chronic inflammatory airway disease.

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Novel Quinazolin‐4(3H)‐one/Schiff Base Hybrids as Antiproliferative and Phosphodiesterase 4 Inhibitors: Design, Synthesis, and Docking Studies

Abdel‐Rahman

Abdel‐Aziz

Canzoneri

et al. 2014

Archiv der Pharmazie

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A novel series of quinazolin-4(3H)-one/Schiff base hybrids was rationally designed and synthesized. The prepared compounds were evaluated for in vitro activity to inhibit phosphodiesterase 4 (PDE4), where several of them showed good-to-moderate activity compared to rolipram. Compound 7 showed potent PDE4 inhibition in this series, with an IC50 of 1.60 µM. Compounds that showed PDE4 inhibition were further assessed for antiproliferative activity using different human tumor cell lines. Compound 10 exhibited significant antiproliferative activity with IC50 values of 140, 79, and 320 nM in breast, lung, and colon tumor cells, respectively. Docking of compound 7 in the active site of PDE4B illustrates its possible binding mode and provides insight for further optimizations of this novel scaffold for inhibiting PDE4.

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PDE4: A Novel Target in the Treatment of Chronic Obstructive Pulmonary Disease

Cited by 70 publications

References 75 publications

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Clinical application of expectorant therapy in chronic inflammatory airway diseases (Review)

Novel Quinazolin‐4(3H)‐one/Schiff Base Hybrids as Antiproliferative and Phosphodiesterase 4 Inhibitors: Design, Synthesis, and Docking Studies

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