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 (ET(R)A and ET(R)B). The aim of this study was to analyze the ET-1/ET(R) 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 ET(R)A 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 ET(R)A negative Panc-1 cells was not decreased. In vivo, the selective ET(R)A inhibition resulted in reduced angiogenesis as measured by lower microvessel densities (MiaPaCa-2: -47%; AsPC-1: -55%). The blockade of ET(R)A 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. ET(R)A blockade did not show an effect on ET(R)A negative Panc-1 tumors. Therefore, targeting ET(R)A with a selective antagonist might provide a new approach to reducing proliferation and angiogenesis in human pancreatic cancer.
Bhargava
Sarah
S
Department of Surgery, Charité-Medical School Berlin, Campus Benjamin Franklin, Berlin, Germany.
Stummeyer
Till
T
Hotz
Birgit
B
Hines
O Joe
OJ
Reber
Howard A
HA
Buhr
Heinz J
HJ
Hotz
Hubert G
HG
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011336:Probability; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D044022:Receptor, Endothelin A / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
C405519:BSF 302146; D001559:Benzhydryl Compounds; D014408:Biomarkers, Tumor; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A