Nitric Oxide Synthase (NOS) Inhibitors in Cancer Angiogenesis

Abstract

Nitric Oxide (NO) is the smallest known molecule in the mammalian biological signaling system. It is well established in the field of molecular biology as an endothelium derived growth factor. It is biosynthesized from L-arginine by three enzyme isoforms - endothelial NOS (eNOS or NOS3), neuronal NOS (nNOS or NOS1) and inducible NOS (iNOS or NOS2). In last two decades, all these enzyme isoforms were investigated to understand their roles in different pathological conditions. The relation between these enzymes and cancer is ambiguous and complex as NOS enzymes have been found to be both pro- and anti-tumorigenic. Although the exact functions of NOS enzymes in cancer progression is still under investigation, some recent reports repeatedly highlighted roles of iNOS and eNOS enzymes in the development of angiogenesis in cancer. As per the latest reports, eNOS should be the most important NOS isoform involved in angiogenesis. The current review highlights the aspect and latest developments of NOS inhibitors as anti-angiogenic agents in cancer. In addition, we report molecular modeling analyses (2D and 3D QSAR, pharmacophore modeling and molecular docking) of some reported eNOS inhibitors to understand structural requirements of these molecules for higher activity. Keywords: Angiogenesis, cancer, molecular docking, NOS inhibitors, pharmacophore mapping, 2D QSAR.