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Role of the endothelin axis and its antagonists in the treatment of cancer.

ABSTRACT: The endothelins (ET) are a group of proteins that act through G-protein coupled receptors. Endothelin-1 (ET-1) was initially identified as a potent vasoconstrictor and dysregulation of the ET axis contributes to pathological processes responsible for cardiovascular disease states. More recently, the ET axis, in particular ET-1 acting through the endothelin A receptor (ET(A) ), has been implicated in the development of several cancers through activation of pathways involved in cell proliferation, migration, invasion, epithelial-mesenchymal transition, osteogenesis and angiogenesis. The endothelin B receptor (ET(B) ) may counter tumour progression by promoting apoptosis and clearing ET-1; however, it has recently been implicated in the development of some tumour types including melanomas and oligodendrogliomas. Here, we review emerging preclinical and clinical data outlining the role of the ET axis in cancer, and its antagonism as an attractive and challenging approach to improve clinical cancer management. Clinical data of ET(A) antagonists in patients with prostate cancer are encouraging and provide promise for new ET(A) antagonist-based treatment strategies. Given the unexpected opportunities to affect pleiotrophic tumorigenic signals by targeting ET(A)-mediated pathways in a number of cancers, the evaluation of ET-targeted therapy in cancer warrants further investigation.

SUBMITTER: Bagnato A

PROVIDER: S-EPMC3087127 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Role of the endothelin axis and its antagonists in the treatment of cancer.

Bagnato A A Loizidou M M Pflug B R BR Curwen J J Growcott J J

British journal of pharmacology 20110501 2

The endothelins (ET) are a group of proteins that act through G-protein coupled receptors. Endothelin-1 (ET-1) was initially identified as a potent vasoconstrictor and dysregulation of the ET axis contributes to pathological processes responsible for cardiovascular disease states. More recently, the ET axis, in particular ET-1 acting through the endothelin A receptor (ET(A) ), has been implicated in the development of several cancers through activation of pathways involved in cell proliferation, ...[more]

PMID: 21232046

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Project description:BackgroundPulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension.ObjectivesTo evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension.Search methodsWe searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012.Selection criteriaWe included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension.Data collection and analysisFive review authors independently selected studies, assessed study quality and extracted data.Main resultsWe included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide.Authors' conclusionsEndothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.

Dataset Information

Role of the endothelin axis and its antagonists in the treatment of cancer.

Publications

Role of the endothelin axis and its antagonists in the treatment of cancer.

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