Abstract B190: Efficacy of the specific ETA receptor antagonist zibotentan (ZD4054) in cancer cells and fibroblasts from colorectal cancer

Endothelin‐1 (ET‐1) contributes to growth and progression of solid cancers, mainly through endothelin receptor A (ETAR). Therefore endothelin receptor antagonism is emerging as a potential treatment for neoplasms. We evaluated the efficacy of the specific ETAR antagonist zibotentan (ZD4054) in blocking ET‐driven cellular effects in colorectal cancer (CRC). CRC cell lines (HT29, SW620) and primary normal fibroblast strains isolated from human colorectal tissues (CF36, CF56, CF65, CF75) were incubated in ET‐1 with/without BQ123, zibotentan (ETAR antagonists), BQ788 (ETBR antagonist). Resultant cell growth was measured by the colourimetric methylene blue assay; migration by a modified monolayer scratch assay; contraction in collagen gels; downstream effectors by western blotting. ET‐1 driven growth (18%–45% above control) was significantly inhibited (p BQ123; CRC and fibroblasts); (2) collagen XI was blocked by ETAR>ETBR antagonism (zibotentan>BQ123; fibroblasts). The specific ETAR antagonist zibotentan is at least as efficacious as BQ123 in blocking ET‐1 driven growth, migration and contraction both in CRC cells and colorectal fibroblasts, which form the supporting tumor stroma. Zibotentan is a strong candidate for adjuvant treatment in CRC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B190.