Endothelin-Receptor Antagonists beyond Pulmonary Arterial Hypertension: Cancer and Fibrosis.

The endothelin axis and in particular the two endothelin receptors, ETA and ETB, are targets for therapeutic intervention in human diseases. Endothelin-receptor antagonists are in clinical use to treat pulmonary arterial hypertension and have been under clinical investigation for the treatment of several other diseases, such as systemic hypertension, cancer, vasospasm, and fibrogenic diseases. In this Perspective, we review the molecules that have been evaluated in human clinical trials for the treatment of pulmonary arterial hypertension, as well as other cardiovascular diseases, cancer, and fibrosis. We will also discuss the therapeutic consequences of receptor selectivity with regard to ETA-selective, ETB-selective, or dual ETA/ETB antagonists. We will also consider which chemical characteristics are relevant to clinical use and the properties of molecules necessary for efficacy in treating diseases against which known molecules displayed suboptimal efficacy

The subconvexity problem for \GL_{2}

Generalizing and unifying prior results, we solve the subconvexity problem for the $L$-functions of \GL_{1} and \GL_{2} automorphic representations over a fixed number field, uniformly in all aspects. A novel feature of the present method is the softness of our arguments; this is largely due to a consistent use of canonically normalized period relations, such as those supplied by the work of Waldspurger and Ichino--Ikeda.Comment: Almost final version to appear in Publ. Math IHES. References updated

Expansion in perfect groups

Let Ga be a subgroup of GL_d(Q) generated by a finite symmetric set S. For an integer q, denote by Ga_q the subgroup of Ga consisting of the elements that project to the unit element mod q. We prove that the Cayley graphs of Ga/Ga_q with respect to the generating set S form a family of expanders when q ranges over square-free integers with large prime divisors if and only if the connected component of the Zariski-closure of Ga is perfect.Comment: 62 pages, no figures, revision based on referee's comments: new ideas are explained in more details in the introduction, typos corrected, results and proofs unchange

Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure

Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a “MITF‐high” phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance “AXL‐high” phenotype. > 50% of melanomas progress with enriched “AXL‐high” populations, and because AXL is linked to de‐differentiation and invasiveness avoiding an “AXL‐high relapse” is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF‐induced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK re‐activation in a paracrine manner. Most importantly, EDN1 not only supports MITF‐high populations through the endothelin receptor B (EDNRB), but also AXL‐high populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXL‐high‐expressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXL‐high cells

Increased endothelin-1 in colorectal cancer and reduction of tumour growth by ET A receptor antagonism

Endothelin-1 (ET-1) is a vasoconstrictor peptide which stimulates proliferation in vitro in different cell types, including colorectal cancer cells. Raised ET-1 levels have been detected both on tissue specimens and in the plasma of patients with cancers. To investigate the role of ET-1 in colorectal cancer: (i) ET-1 plasma levels in patients with colorectal cancer were measured by radioimmunoassay: group 1 = controls (n = 22), group 2 = primary colorectal cancer only (n = 39), group 3 = liver metastases only (n = 26); (ii) ET-1 expression in primary colorectal cancer specimens (n =10) was determined immunohistochemically and (iii) the effect of intraportally infused antagonists to the two ET-1 receptors, ET A and ET B, on the growth of liver metastases in a rat model was assessed. ET-1 plasma levels were significantly increased in both patients with primary tumour and patients with metastases, compared to controls (P < 0.01, 3.9 ± 1.4, 4.5 ± 1.5, vs. 2.75 ± 1.37 pg/ml, respectively). Immunohistochemically, strong expression of ET-1 was found in the cytoplasm, stroma and blood vessels of cancers, unlike the normal colon where only the apical layer of the epithelium, vascular endothelial cells and surrounding stroma were positively stained. In the rat model, there was significant reduction in liver tumour weights compared to controls, following treatment with the ET A antagonist (BQ123) 30 min after the intraportal inoculation of tumour cells (P < 0.05). These results suggest ET-1 is produced by colorectal cancers and may play a role in the growth of colorectal cancer acting through ET A receptors. ET A antagonists are indicated as potential anti-cancer agents. © 2001 Cancer Research Campaign http://www.bjcancer.co

Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells

Endothelin (ET)-1 can act as an autocrine/paracrine growth factor or an antiapoptotic factor in human cancers. To study the role of ET-1 in human colon cancer, proliferation and apoptosis of colon carcinoma cells was investigated using human HT-29 and SW480 colon carcinoma cells. ET-1 was secreted by these cells. Treatment of cells with bosentan, a dual ET(A/B)-receptor antagonist, decreased cell number. Inhibition of DNA synthesis by bosentan was observed only in the presence of serum. Exogenously added ET-1 did not increase DNA synthesis in serum-deprived cells. SW480 cells were sensitive and HT-29 cells were resistant to FasL-induced apoptosis. Bosentan sensitised resistant HT-29 cells to FasL-induced, caspase-mediated apoptosis, but not to TNF-alpha-induced apoptosis. Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or FLIP. Bosentan sensitisation to apoptosis was reversed by low concentrations (10(-13)-10(-10) M), but not by high concentrations (10(-9)-10(-7) M) of ET-1. These results suggest that the binding of ET-1 to high-affinity sites inhibits FasL-induced apoptosis, while the binding of either ET-1 or receptor antagonists to low-affinity sites promotes FasL-induced apoptosis. In conclusion, endothelin signalling pathways do not induce human colon cancer cell proliferation, but are survival signals controling resistance to apoptosis

Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension

Background: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats. Methods: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed. Results: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling. Conclusion: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension