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 ¼ 4) and fibroblast strains (n ¼ 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.

Efficacy of Zibotentan in Colorectal Cancer—Letter

“…Interestingly, they demonstrate that ETAR is the principal receptor used by ET-1 and provide evidence for involvement of stromal fibroblasts in cancer progression as targets of ET-1 signaling. Given zibotentan had the greatest inhibitory effect on ET-1 signaling, the authors suggest a potential role of the drug in adjuvant therapy of colorectal cancer (1). These data are further confirmed by more recent evidence that ET-1 signaling through ETAR promotes liver metastasis in colorectal cancer (2).…”

“…Results from the ongoing phase II study of zibotentan added to FOLFIRI for patients with metastatic colorectal cancer are eagerly awaited. Notably, given preclinical implications for an antimetastatic role of zibotentan (1,2), the design of a study testing the drug in the adjuvant setting as an adjunct to established regimens would also be helpful to decipher whether intervention to the endothelin axis in colorectal cancer may actually delay relapse of disease. …”

Aspects of the endothelin system in colorectal cancer

“…Endothelin-1 is overexpressed in many gastrointestinal tumors including colorectal and gas tric cancers (28). Increased expression of EDN-1 was demonstrated by immunohistochemistry and immune-electron-microscopy in colorectal cancer primaries and liver metastases, as well as in endothelial and stromal cells (29,30).…”

“…The former two enzymes stimulate protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K), and this leads to stimulation of the mitogen activating protein kinase (MAPK) pathway (28). In colorectal cancer patients there is up-regulation of EDNRA and down-regulation of EDNRB, which has bearing on the AKT pathway.…”

“…The increases in TIMP-1 and MMP-2 can be blocked by an EDNRA blocker more than an EDNRB blocker (56). Fibroblast cells isolated from normal tissue adjacent to colon cancer expressed EDNRA and EDNRB (28). In vitro, EDN-1 can stimulate growth, migration, contraction and the production of ECM-modifying proteins of fibroblasts, which were isolated from normal tissues adjacent to colon cancers (56).…”