Glycine as a potent anti-angiogenic nutrient for tumor growth

Accumulating lines of evidence suggest a possibility that glycine is useful as an immuno-modulating amino acid. Glycine most likely prevents the lipopolysaccharide (LPS)-induced elevation of intracellular Ca2+ concentration in Kupffer cells, thereby minimizing LPS receptor signaling and cytokine production. Moreover, it was reported that dietary glycine inhibits the growth of tumors. Vascular endothelial growth factor (VEGF) plays a critical role in cancer progression by promoting new blood vessel formation. Activation of VEGF receptor has been shown to result in activation of phospholipase C-gamma and increases in intracellular Ca2+ concentration. The VEGF-induced cell proliferation is dependent on intracellular Ca2+ concentration. The effects of glycine on VEGF-induced increases in intracellular Ca2+ concentration in endothelial cell line (CPA) were studied. The VEGF increased intracellular Ca2+ concentration rapidly, but glycine blunted increases in intracellular Ca2+ concentration due to VEGF. Further, the inhibitory effects of glycine were prevented by low concentrations of strychnine (1 mu mol/L) or incubation with chloride-free buffer. Moreover, glycine increased influx of radiolabeled chloride into CPA cells approximately 10-fold. Furthermore, mRNA 92% identical to the beta-subunit of the glycine-gated chloride channel from spinal cord was identified in endothelial cells using reverse transcription-polymerase chain reaction. Finally, glycine significantly diminished serum-stimulated proliferation and migration of endothelial cells. These data indicate that the inhibitory effect of glycine on growth and migration of endothelial cells is due to activation of a glycine-gated chloride channel. This hyperpolarizes the cell membrane and blocks influx of Ca2+, thereby minimizing growth factor-mediated signaling. Therefore, glycine can be used not only for treatment of inflammation, but also for chemoprevention and treatment of carcinoma.