Dietary Glycine Inhibits Angiogenesis During Wound Healing and Tumor Growth

Abstract

In this study we investigated the effects of glycine on angiogenesis during embryogenesis, wound healing and tumor growth. In chorioallantoic membrane (CAM) assay, glycine (100 µM) inhibited angiogenesis by more than 50%. We studied dietary glycine's effect on fibrin induced wound healing response in a novel (Fibrin Z-chamber) assay. Fibrin within the chamber triggers the healing cascade leading to formation of granulation tissue (GT) rich in blood vessels and stroma. GT was reduced by more than 30% (p < 0.0001) in dietary Glycine groups as compared to control. We found that microvessel density dropped significantly (15%, p < 0.0003) with dietary glycine whereas the other components of GT were unaffected. We evaluated tumor growth delay utilizing Tumor Z-Chamber (fibrin with R3230 mammary adenocarcinoma cells) since tumors take advantage of angiogenesis and matrix formation. We observed that tumor growth decreased by 15% (p < 0.03) and tumor microvessel density dropped by 20% (p < 0.03) with dietary glycine compared to controls. We found that iNOS protein levels were decreased significantly in both GT (24%-57%) and tumor tissue (19-75%). In conclusion, we found that dietary glycine is a potent anti-angiogenic agent that can reduce wound healing and tumor growth through reduction of iNOS expression.

Glycine inhibits angiogenesis in colorectal cancer: role of endothelial cells

“…Glycine treatment was shown to inhibit HUVEC growth and suppress both migration and capillary formation after VEGF stimulation in vitro. These findings strongly support glycine's role as direct inhibitor of angiogenesis and are consistent with previously reported findings on the migration and proliferation of bovine endothelial cells (Amin et al 2003). This was reproducible with endothelial cell stimulation using conditioned medium which was collected from human colorectal cancer cells that are known to overexpress VEGF (Fig.…”

“…Moreover, glycine has been shown to prevent Kupffer-cell-dependent liver injury in models of acute liver injury and in chemotherapy models Mikalauskas et al 2011). The indirect effects of glycine have already been demonstrated in various settings: in hepatocellular carcinoma, glycine down-regulates VEGF expression via GlyR, and both melanoma and mammary tumors have been impacted by the presence of glycine, in vivo (Amin et al 2003;Bruns et al 2014;Rose et al 1999a, b). In our study, we identified a direct anti-angiogenic effect on endothelial cells that was regulated via GlyR.…”

“…Scratch/migration assays were carried out using six independent experiments and four randomly chosen photomicrographs were analyzed per experiment (n = 24/group). Gly glycine, h hours, Str strychnine, *p < 0.05 in both in vitro and in vivo experiments, the indirect and direct anti-angiogenic effects of glycine have been studied (Amin et al 2003;Bruns et al 2014;Rose et al 1999a, b). There is strong evidence that glycine both down-regulates VEGF production in tumor cells and inhibits endothelial cell growth via GlyR-which seems to be present on both tumor and endothelial cells (Bruns et al 2014;Yamashina et al 2001Yamashina et al , 2007.…”

“…Besides being a major inhibitory neurotransmitter via the activation of the glycine receptor (GlyR) in central nervous system, glycine has been shown to protect against acute liver injury that occurs after warm or cold ischemia, or after toxic liver injury possibly resulting from the chemotherapy regimens commonly used for CRC Hoffmann et al 2011;Mikalauskas et al 2011;Schindler et al 2009;Zhong et al 2003;Schemmer et al 2002;Wheeler et al 1999;Amin et al 2003). Glycine has anti-angiogenic effects on wound healing, induced liver tumors, melanoma, and mammary cancer, in vivo (Amin et al 2003;Rose et al 1999a, b). Recently, the indirect anti-angiogenic impact of glycine on hepatocellular carcinoma was identified in an in vitro model (Bruns et al 2014).…”

Noninvasive In vivo Detection of Glutathione Metabolism in Tumors

“…Glycine infusion at either dose level does not seem to affect rat well-being and, at the lower dose, does not perturb blood counts or electrolyte values. Lower doses may be preferential because rats fed a glycine-rich diet for 5 to 12 days show an inhibition of tumor angiogenesis (14). At this time, it is not known if the i.v.…”