Fig. 1. Schematic diagram representing the mechanism(s) by which methylnaltrexone inhibits angiogenesis. Vascular endothelial growth factor (VEGF) binding to VEGF receptors induces Src activation, Src-mediated Akt, RhoA, and mammalian target of rapamycin (mTOR) activation and consequent endothelial cell proliferation, migration, and actin cytoskeletal reorganization required for angiogenesis. Methylnaltrexone (MNTX) inhibits the μ-opioid receptor (MOR) and promotes tyrosine phosphatase activity, leading to Src inactivation. This promotes Akt, RhoA, and mTOR inactivation and consequent inhibition of angiogenesis.