Targeting the endothelin system: Novel therapeutic options in gynecological, urological and breast cancers

The endothelin system comprises the three pepticle hormones endothelin (ET)-1, -2, -3, their G protein-coupled receptors, endothelin-A-receptor (ET_AR) and endothelin-B-receptor (ET_BR), and the enzymes of endothelin biosynthesis and degradation. In the past two decades, an impressive amount of data has been accumulated investigating the role of the endothelin system in a variety of malignancies. In many cancers, ET-1/ET_AR interaction induces proliferation, angiogenesis, antiapoptosis and resistance to chemotherapy. Data indicate a pivotal role of the endothelin system in tumorigenesis, local progression and metastasis. Subsequently, novel drugs have been designed inhibiting ET-1 biosynthesis or ET_AR interaction. A wide range of preclinical data is available on the role of ET_AR antagonists in gynecological, urological and breast cancers providing evidence for their antiangiogenic, proapoptotic and growth inhibitory effects. Of particular interest is the anti-invasive and antimetastatic efficacy of ET_AR antagonists and synergism when co-administered with established cancer therapies. Data indicate a future role of ET_AR antagonists in oncologic therapies.