Notch antagonists: Potential modulators of cancer and inflammatory diseases

Notch is a key player in various developmental<br> processes during the embryonic stage as well as in regulating<br> tissue homeostasis, cell differentiation, and stem cell maintenance<br> in adult life. Activation of Notch signaling occurs following<br> Notch receptor−ligand interaction and subsequent enzymatic<br> proteolysis by the gamma-secretase complex, resulting in the<br> cytoplasmic release of a Notch intracellular domain, which<br> translocates to the nucleus to initiate the downstream transcrip-<br> tional machinery. Notch activation and its aberrant signaling have<br> been broadly linked to the pathogenesis of cancer and some<br> chronic inflammatory diseases resulting in pathologic fibrotic<br> processes. This review focuses on the molecular basis of Notch-<br> induced signaling and its interaction with other pathways to<br> identify therapeutic targets. We also highlight current efforts to pharmacologically intervene in Notch signaling and discuss promising ongoing experimental and clinical studies.