Dietary glycine decreases both tumor volume and vascularization in a combined colorectal liver metastasis and chemotherapy model

Juste Maneikyte^1,2, Augustinas Bausys^1,2,3, Bettina Leber¹, Angela Horvath⁴, Nicole Feldbacher¹, Gerald Hoefler⁵, Kestutis Strupas², Philipp Stiegler¹, Peter Schemmer^1✉

1. General, Visceral and Transplant Surgery, Dept. of Surgery, Medical University of Graz, Austria
2. Faculty of Medicine, Vilnius University, Lithuania
3. National Cancer Institute, Vilnius, Lithuania
4. Gastroenterology and Hepatology, Dept. of Internal Medicine, Medical University of Graz, Austria
5. Diagnostic and Research Institute of Pathology, Medical University of Graz, Austria

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Citation:
Maneikyte J, Bausys A, Leber B, Horvath A, Feldbacher N, Hoefler G, Strupas K, Stiegler P, Schemmer P. Dietary glycine decreases both tumor volume and vascularization in a combined colorectal liver metastasis and chemotherapy model. Int J Biol Sci 2019; 15(8):1582-1590. doi:10.7150/ijbs.35513. Available from https://www.ijbs.com/v15p1582.htm

Abstract

Rationale: Chemotherapy (CTx) with FOLFOX is indicated prior to resection of liver metastases; however, its effect is limited due to chemoresistance and its toxicity prevents from aggressive surgery needed in some cases. Hepatoprotective glycine has been shown to have anti-tumorigenic properties in various cancers. Thus, this study was designed to evaluate the effects of glycine combined with FOLFOX on colorectal liver metastases (CRLM).

Methods: The effect of glycine combined with 5-fluorouracil and oxaliplatin was investigated in vitro on colorectal cancer (CC531). Further, Wag/Rij rats with CRLM were treated with 5% dietary glycine ± FOLFOX. µCT liver scan, anti-Ki67, and anti-CD31 were compared.

Results: Glycine alone and combined with CTx has no effect on both CC531 viability in vitro and tumor proliferation in vivo; however, glycine significantly decreased tumor volume to about 42-35% of controls in vivo (p<0.05) with a 60% decreased tumor microvascular density (MVD) (p=0.004). Further glycine doesn't counteract anti-tumor properties of CTx.

Conclusions: This study nicely demonstrates that glycine inhibits the growth of CRLM and does not decrease CTx effectiveness. Underlying mechanisms most likely include a decreased tumor MVD. Clinical trials are warranted to implement non-toxic hepatoprotective glycine in novel anti-cancer strategies in humans.

Keywords: Glycine, FOLFOX, colorectal liver metastasis