title: Efficacy of the specific endothelin a receptor antagonist zibotentan (ZD4054) in colorectal cancer: a preclinical study.
abstract: Endothelin 1 (ET-1) is overexpressed in cancer, contributing to disease progression. We previously showed that ET-1 stimulated proliferative, migratory, and contractile tumorigenic effects via the ET(A) receptor. Here, for the first time, we evaluate zibotentan, a specific ET(A) receptor antagonist, in the setting of colorectal cancer, in cellular models. Pharmacologic characteristics were further determined in patient tissues. Colorectal cancer lines (n = 4) and fibroblast strains (n = 6), isolated from uninvolved areas of colorectal cancer specimens, were exposed to ET-1 and/or ET(A)/(B) receptor antagonists. Proliferation (methylene blue), migration (scratch wounds), and contraction (gel lattices) were assessed. Receptor distribution and binding characteristics (K(d), B(max)) were determined using autoradiography on tissue sections and homogenates and cytospun cells, supported by immunohistochemistry. Proliferation was inhibited by ET(A) (zibotentan > BQ123; P < 0.05), migration by ET(B) > ET(A), and contraction by combined ET(A) and ET(B) antagonism. Intense ET-1 stromal binding correlated with fibroblasts and endothelial cells. Colorectal cancer lines and fibroblasts revealed high density and affinity ET-1 binding (B(max) = 2.435 fmol/1 × 10(6) cells, K(d) = 367.7 pmol/L; B(max) = 3.03 fmol/1 × 10(6) cells, K(d) = 213.6 pmol/L). In cancer tissues, ET(A) receptor antagonists (zibotentan; BQ123) reduced ET-1 binding more effectively (IC(50): 0.1-10 μmol/L) than ET(B) receptor antagonist BQ788 (∼IC(50), 1 mmol/L). ET-1 stimulated cancer-contributory processes. Its localization to tumor stroma, with greatest binding/affinity to fibroblasts, implicates these cells in tumor progression. ET(A) receptor upregulation in cancer tissues and its role in tumorigenic processes show the receptor's importance in therapeutic targeting. Zibotentan, the most specific ET(A) receptor antagonist available, showed the greatest inhibition of ET-1 binding. With its known safety profile, we provide evidence for zibotentan's potential role as adjuvant therapy in colorectal cancer.
authors.affiliation: Cancer Nanotechnology Group, UCL Division of Surgery and Interventional Science, Royal Free Hospital, UK.
authors.forename: Samer-ul
authors.initials: SU
authors.lastname: Haque
authors.forename: Michael R
authors.initials: MR
authors.lastname: Dashwood
authors.forename: Mohammed
authors.initials: M
authors.lastname: Heetun
authors.forename: Xu
authors.initials: X
authors.lastname: Shiwen
authors.forename: Noreen
authors.initials: N
authors.lastname: Farooqui
authors.forename: Bala
authors.initials: B
authors.lastname: Ramesh
authors.forename: Hazel
authors.initials: H
authors.lastname: Welch
authors.forename: Felicity J
authors.initials: FJ
authors.lastname: Savage
authors.forename: Olagunju
authors.initials: O
authors.lastname: Ogunbiyi
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
authors.forename: Marilena
authors.initials: M
authors.lastname: Loizidou
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D011485:Protein Binding; D021381:Protein Transport; D011759:Pyrrolidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C511404:ZD4054