Selective Inhibition of Endothelin Receptor A as an Anti-angiogenic and Anti-proliferative Strategy for Human Pancreatic Cancer

Endothelin-1 (ET-1) plays a major role in tumor proliferation and angiogenesis of various types of cancer acting through endothelin receptors A and B (ETRA and ETRB). The aim of this study was to analyze the ET-1/ETR system in human pancreatic cancer cell lines and to evaluate the effect of a selective endothelin A inhibitor in vitro and in vivo in an orthotopic mouse model. Three different human pancreatic cancer cell lines, MiaPaCa-2, AsPC-1, and Panc-1, were studied. We found that proliferation of human pancreatic carcinoma cells expressing ETRA was significantly reduced with a selective antagonist. Hypoxic conditions led to improved results compared to a normoxic environment (MiaPaCa-2: −53% vs. −18%; AsPC-1: −54% vs. −46%). Proliferation of ETRA negative Panc-1 cells was not decreased. In vivo, the selective ETRA inhibition resulted in reduced angiogenesis as measured by lower microvessel densities (MiaPaCa-2: −47%; AsPC-1: −55%). The blockade of ETRA decreased the volume (MiaPaCa-2: −87%; AsPC-1: −28%) and metastatic spread (MiaPaCa-2: −95.5%; AsPC-1: −27%) of receptor-positive tumors, thereby increasing survival in experimental pancreatic cancer. ETRA blockade did not show an effect on ETRA negative Panc-1 tumors. Therefore, targeting ETRA with a selective antagonist might provide a new approach to reducing proliferation and angiogenesis in human pancreatic cancer.