Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist

Clozel, Martine; Breu, Volker; Burri, K.; Cassal, J.-M.; Fischli, Walter; Gray, Gillian A.; Hirth, Georges; Löffier, Bernd-Michael; Müller, Marcel; Neidhart, Werner; Ramuz, Henri

doi:10.1038/365759a0

Cited by 514 publications

(205 citation statements)

References 31 publications

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“…However, activation of the ET-1 pathway was a necessary permissive signal for colon carcinoma cell survival. This information is in agreement with our previous observation that in induced colon carcinomatosis in the rat, bosentan, a dual ET A /ET B -receptor antagonist (Clozel et al, 1993), has the potential to reduce initial tumour growth (Peduto-Eberl et al, 2000;Egidy et al, 2000). In human colon carcinoma cells, bosentan induced low levels of apoptosis in SW480 cells and potentiated FasL-mediated apoptosis in FasL-resistant HT-29 cells.…”

Section: Discussionsupporting

confidence: 92%

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

2003

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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 FasLinduced apoptosis. Bosentan sensitised resistant HT-29 cells to FasL-induced, caspase-mediated apoptosis, but not to TNF-a-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 À13 -10 À10 M), but not by high concentrations (10 À9 -10 À7 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.

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Section: Discussionsupporting

confidence: 92%

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

2003

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“…Bosentan (Clozel et al, 1993), a mixed ET A /ET B receptor antagonist, induced apoptosis in all glioblastoma cell lines in a dose-dependent manner, but potentiated FasL-mediated apoptosis only in the LNZ308 cells, at concentrations below those needed to induce apoptosis with bosentan alone. In LN18 cells, FasL induced death in the absence of bosentan, whereas in LN215 and LN319 cells, FasL had no effect.…”

Section: Discussionmentioning

confidence: 99%

The Endothelin System in Human Glioblastoma

Egidy

Eberl

Valdenaire

et al. 2000

Laboratory Investigation

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SUMMARY:Endothelin-1 (ET-1) is a powerful mitogenic and/or anti-apoptotic peptide produced by many cancer cells. To evaluate the potential role of the endothelin system in glioblastoma we first determined the cellular distribution of the mRNA and proteins of the components of the endothelin system, preproendothelin-1 (PPET-1), endothelin-converting enzyme-1 (ECE-1), and ET A and ET B receptors in human glioblastoma tissue and glioblastoma cell lines. PPET-1, ECE-1, and ET A receptor were highly expressed in glioblastoma vessels and in some scattered glioblastoma areas whereas ET B receptor was mainly found in cancer cells. This suggests that glioblastoma vessels constitute an important source of ET-1 that acts on cancer cells via the ET B receptor. Four human glioblastoma cell lines expressed mRNA for all of the components of the ET-1 pathway. Bosentan, a mixed ET A and ET B receptor antagonist, induced apoptosis in these cell lines in a dose-dependent manner. Apoptosis was potentiated by Fas Ligand (APO-1L, CD95L), a pro-apoptotic peptide, only in LNZ308 cells, corresponding to the known functional Fas expression in these cell lines. LNZ308 cells also expressed the long and short forms of the cellular FLICE/caspase-8 inhibitory protein (FLIP). Bosentan and a protein kinase C inhibitor down-regulated short FLIP in these cells. ET-1 induced transient phosphorylation of extracellular signal-regulated kinase but did not induce long-term thymidine incorporation in LNZ308 glioblastoma cells. These results suggest that, in glioblastoma cells, ET-1, mainly acting via the ET B receptor, is a survival/antiapoptotic factor produced by tumor vasculature, but not a proliferation factor, involving protein kinase C and extracellular signal-regulated kinase pathways, and stabilization of the short form of FLIP. (Lab Invest 2000, 80:1681-1689.

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“…We have already described Ro 46-2005 and bosentan (Ro 47-0203) as the first synthetic non-peptide mixed antagonists of ET receptors [6,7]. We are now describing [8] …”

Section: Introductionmentioning

confidence: 99%

The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

Clozel

Breu

1996

FEBS Letters

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We used Ro 46-8443, non-peptidic antagonist selective of endothelin ETB receptors, to study the role of ET8 receptors in rat hypertension models. In normotensive rats, Ro 46-8443 decreased blood pressure, but in SHR and DOCA rats, it induced a pressor effect, due to blockade of ETs-mediated release of nitric oxide since L-NAME prevented it. In rats rendered hypertensive by chronic L-NAME, Ro 46-8443 did not induce a pressor but depressor effect. Thus, in DOCA rats and SHR, Ro 46-8443 reveals a predominant influence of endothelial 'vasorelaxant' ETa receptors, while in normotensive rats the prevailing role of ETn receptors seems to be in mediating a vasoconstrictor tone.

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Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist

Cited by 514 publications

References 31 publications

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

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

The Endothelin System in Human Glioblastoma

The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

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Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist

Cited by 514 publications

References 31 publications

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

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

The Endothelin System in Human Glioblastoma

The role of ETB receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ETB receptor antagonist Ro 46‐8443

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The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443