Inhibiting the Enzymes of the Endothelin and Renin-Angiotensin Systems in Cancer

The renin-angiotensin (RAS) and endothelin/ET-1,-2,-3 systems comprise families of precursor peptides, angiotensinogen and big-endothelins respectively, activated by families of proteases. Angiotensinogen is activated by the sequential action of an aspartyl-protease, renin, then a metalloprotease, angiotensin converting enzyme (ACE). Big-endothelins are activated by the metalloproteases endothelin converting enzyme/ECE-1a-d, and to a lesser extent neprilysin (NEP/CD10). These proteolytic cascades produce the system-representative active peptides angiotensin II (Ang II) and endothelin-1 (ET-1). Then several exopeptidases, which include aminopeptidases or carboxypeptidases, and endopeptidases, in particular NEP, further process these active peptides to either inactive fragments or intermediate peptides with various biological activities. The RAS and ET systems have been mainly studied in the context of cardiovascular disorders, and either agonists or antagonists of their receptors, and inhibitors for the enzymes metabolizing the precursors and/or the active peptides have been developed for the treatment of these disorders. However, the RAS and ET systems, in addition to controlling the vascular tone and natriohydric balance, may be involved in cell growth and/or death in cancer, fibrotic or degenerative diseases. Therefore the protease inhibitors developed for treating cardiovascular disorders may have wider application in cancer than initially envisioned, which will be reviewed in this manuscript