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.

Figure 1

Endothelin-1 (ET-1) signalling through the endothelin A receptor (ET_A) in cancer cells (Bagnato and Rosanò, 2008). Reprinted with permission from Elsevier. AA, arachidonic acid; COX-1, cyclo-oxygenase 1; COX-2, cyclo-oxygenase 2; DAG, diacylglycerol; EGFR, epidermal growth factor receptor; ET_AR, endothelin A receptor; Gq, G protein q; GSK-3, glycogen synthase kinase-3; HIF-1α, hypoxia-inducible factor 1-α; ILK, integrin-linked kinase; IP3, inositol 1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MEK, mitogenactivated protein kinase/extracellular signal-regulated kinase kinase; mTOR, mammalian target of rapamycin; PGE₂, prostaglandin E₂; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLA₂, phospholipase A₂; PLC, phospholipase C; PTK, protein-tyrosine kinase; VEGF, vascular endothelial growth factor.

Figure 2

Time to disease progression following treatment with atrasentan in men with (A) metastatic and (B) non-metastatic castration-resistant prostate cancer (Carducci et al., 2007; Nelson et al., 2008). Reprinted with permission from John Wiley and Sons.

Figure 3

(A) Time to progression and (B) overall survival of patients with castration-resistant prostate cancer treated with zibotentan or placebo (final analysis) (James et al., 2010). Reprinted with permission from John Wiley and Sons.