TY - JOUR
T1 - Role of the endothelin axis and its antagonists in the treatment of cancer
AU - Bagnato, A.
AU - Loizidou, M.
AU - Pflug, B. R.
AU - Curwen, J.
AU - Growcott, J.
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
KW - cancer
KW - endothelin
KW - endothelin antagonist
KW - endothelin receptor
KW - ET receptor
KW - ET receptor
KW - GPCR
KW - zibotentan
UR - http://www.scopus.com/inward/record.url?scp=79954456308&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79954456308&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2011.01217.x
DO - 10.1111/j.1476-5381.2011.01217.x
M3 - Article
C2 - 21232046
AN - SCOPUS:79954456308
VL - 163
SP - 220
EP - 233
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 2
ER -