Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

Kohan, Donald E.; Cleland, John G.F.; Rubin, Lewis J.; Theodorescu, Dan; Barton, Matthias

doi:10.1016/j.lfs.2012.07.034

Cited by 82 publications

(69 citation statements)

References 188 publications

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“…However, this trial was terminated early because avosentan use was associated with a greater incidence of serious adverse cardiovascular events, particularly edema and heart failure. 13,16 These results mimic those in other cardiovascular illnesses in which adverse effects, predominantly fluid overload, limited the usefulness of the drug. In hindsight, the adverse effect profile of ET-1 antagonists should be of no surprise because of the complexity of the ET system.…”

supporting

confidence: 56%

“…Moreover, certain patient populations may be more prone to the adverse effects of ET blockade than others. 16 In the related clinical study, de Zeeuw et al 17 conducted a multicenter, multinational trial that examined the efficacy (reduction of albuminuria) and the adverse effect profile of atrasentan added to renin-angiotensin system inhibitor therapy. It is an extension of a previous dose-response study conducted by Kohan et al 13 in which addition of atrasentan to reninangiotensin system inhibition decreased albuminuria without increasing edema.…”

mentioning

confidence: 99%

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Endothelin Antagonists in Diabetic Nephropathy

Chandrashekar¹,

Juncos

2014

Journal of the American Society of Nephrology

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The pivotal discovery of endothelin (ET) by Yanagisawa and colleagues 1 in 1988 generated wide interest in this peptide, as evidenced by the nearly 27,000 articles published to date that have examined its role in biology. ET is now recognized as essential to the function of various organs and metabolic processes. 2 The ET family consists of three 21-amino acid peptides-ET-1 (ubiquitous and most biologically active), ET-2, and ET-3-that exert their actions via two receptor subtypes: ET A and ET B 2 . Activation of these receptors usually, but not always, incites opposing actions; an additional consideration is that the ET B receptor also acts as a clearance receptor. 3 Consequently, the effects of ET can vary among different organs depending on the amount being formed and on the receptor subtypes present. For instance, in the cardiovascular system ET induces vasoconstriction and growth via ET A receptors and vasodilation and growth inhibition via ET B receptors. 1,3 The net effect results in an increase in systemic vascular resistance and BP. This potentially injurious effect is augmented by ET's ability to stimulate growth factors and cytokines, which induce neutrophil adhesion, platelet aggregation, and formation of extracellular matrix protein. 3 Together, these actions can precipitate a vicious cycle that accelerates hypertension and atherosclerosisinduced vascular disease. 3 Despite its importance in the cardiovascular system, ET plays an even larger role in regulating renal function and injury. This is because the kidneys are exquisitely sensitive to ET-1 (up to 10-fold more than are other organs 4 ) and because the components of the ET system are widely distributed throughout the kidney; ET-1 is present in the renal microvasculature, in all types of glomerular cells, and in the tubules (the renal medulla contains the highest ET-1 levels in the body 5 ). Thus, it is no surprise that ET-1 has such a key role in regulating renal hemodynamics, salt and water homeostasis, and acid-base balance 6 and in modulating cell proliferation, extracellular matrix accumulation, inflammation, and fibrosis. 7 Consequently, any abnormality in the intrarenal ET system may result in renal dysfunction (e.g., salt sensitivity) and/or injury. Indeed, ET may participate in the progression of renal injury during obesity, hypertension, and diabetes. 7 Because most of the deleterious effects of ET-1 appear to be mediated through the ET A receptors, this receptor has become an attractive therapeutic target in various forms of cardiovascular and renal diseases, such as diabetes. 3 Diabetic nephropathy is an attractive target for ET-1 blockade because several lines of evidence implicate ET in this disease. First, the synthesis and/or effects of ET-1 are increased in response to hyperglycemia, hypertensive glomerular injury, and insulin, 8 which results in increased renal expression and systemic circulatory levels of ET-1 in experimental and clinical diabetes. 9,10 Second, abnormalities in the ET system are present in the renal areas tar...

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supporting

confidence: 56%

mentioning

confidence: 99%

Endothelin Antagonists in Diabetic Nephropathy

Chandrashekar¹,

Juncos

2014

Journal of the American Society of Nephrology

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“…Overall, these findings provide important insights in the development of new prognostic tools and will likely lead to an improved treatment for patients with EOC. Our findings also provide a potential explanation as to why the use of selective ET A R antagonists in clinical trials did not achieve satisfactory results (2,(41)(42)(43). Selective ET A R blockade could tilt the balance toward ET B R signaling in the tumor microenvironment, including the recruitment of antitumor T cells (10,11).…”

Section: Discussionmentioning

confidence: 84%

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Rosanò¹,

Cianfrocca²,

Tocci³

et al. 2014

Cancer Research

107

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The high mortality of epithelial ovarian cancer (EOC) is mainly caused by resistance to the available therapies. In EOC, the endothelin-1 (ET-1, EDN1)-endothelin A receptor (ET A R, EDNRA) signaling axis regulates the epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, we define a novel bypass mechanism through which ET A R/b-arrestin-1 (b-arr1, ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that ET A R/b-arr1 activity promoted nuclear complex with b-catenin and p300, resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as ET-1, enhancing the network that sustains chemoresistance. Silencing of b-arr1 or pharmacologic treatment with the dual ET A R/ET B R antagonist macitentan prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo macitentan treatment reduced tumor growth, vascularization, intravasation, and metastatic progression. The combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, indicating that macitentan can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant EOC tissues confirmed increased recruitment of b-arr1 and b-catenin to ET-1 gene promoter. In these tissues, high expression of ET A R significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which ET A R/b-arr1 signaling is integrated with the Wnt/b-catenin pathway to sustain chemoresistance in EOC, and they offer a solid rationale for clinical evaluation of macitentan in combination with chemotherapy to overcome chemoresistance in this setting. Cancer Res; 74(24); 7453-64. Ó2014 AACR.

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“…[162][163][164] ETB IHIBITORS-sitaxsentan, avosentan trial has terminated because of adverse effect.…”

Section: Endothelin Inhibitorsmentioning

confidence: 99%