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

Abstract

The endothelin system comprises the three peptide 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.

Keywords::

• atrasentan
• breast cancer
• ECE
• endothelin system
• ET-1
• ET_AR
• ovarian cancer
• prostate cancer
• RO 67–7447
• ZD4054

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.