Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial

MacNee, William; Allan, Richard; Jones, Ieuan; Salvo, María Cristina De; Tan, Leonard

doi:10.1136/thoraxjnl-2012-202744

Cited by 122 publications

(104 citation statements)

References 21 publications

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“…is an oral p38a-selective inhibitor, which increased trough FEV 1 values and dyspnea at some doses in a 6-week study of 230 patients with COPD (MacNee et al, 2013). Because of the problems of side effects at high oral doses of p38 inhibitors, several inhaled drugs have been developed, but no results in airway disease have been reported ).…”

Section: B P38 Inhibitorsmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

103

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Section: B P38 Inhibitorsmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

103

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“…Since inhibiting the activity of the kinase acutely reduces tumor metastasis, this kinase may also serve as a novel pharmacological target for preventing the immediate spread of tumor cells, for instance during manipulation of a tumor during a surgical procedure. P38K inhibitors were used in clinical trials for other indications, like for example chronic obstructive lung disease and rheumatoid arthritis, and have been show to be well tolerable [61,62]. Thus, inhibition of p38K might be a novel approach to prevent tumor metastasis.…”

Section: Discussionmentioning

confidence: 99%

Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis

Carpinteiro

Beckmann²,

Seitz³

et al. 2016

Cell Physiol Biochem

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Background: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm) from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. Methods: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K), phospholipase Cγ (PLCγ), ezrin, and extracellular signal-regulated kinases. Results: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K), phospholipase Cγ (PLCγ), ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of β1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. Conclusions: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates β1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel target to prevent tumor metastasis.

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“…Therefore development of MAPK inhibitors to treat COPD seems a logical step forward [43]. MacNee and colleagues investigated the efficacy and safety of an oral p38 MAPK inhibitor, PH-797804 (Pfizer, USA), in patients with COPD [44]. In this randomised, DBPC, multicentre trial, 230 patients were randomised to receive placebo, 0.5 mg, 3 mg, 6 mg or 10 mg PH-797804 o.d.…”

Section: Combination Therapymentioning

confidence: 99%

Emerging therapeutic strategies in COPD

Babu

Morjaria

2015

Drug Discovery Today

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Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial

Cited by 122 publications

References 21 publications

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis

Emerging therapeutic strategies in COPD

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