Betaine inhibits in vitro and in vivo angiogenesis through suppression of the NF-κB and Akt signaling pathways

Yi,Eui-Yeun; Kim,Yung-Jin

doi:10.3892/ijo.2012.1616

Betaine inhibits in vitro and in vivo angiogenesis through suppression of the NF-κB and Akt signaling pathways

Authors:
- Eui-Yeun Yi
- Yung-Jin Kim
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Affiliations: Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea
Published online on: August 31, 2012 https://doi.org/10.3892/ijo.2012.1616
Pages: 1879-1885

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Abstract

Angiogenesis is defined as the formation of new blood vessels form existing vessels surrounding a tumor. The process of angiogenesis is an important step for tumor growth and metastasis, as is inflammation. Thus, angiogenesis inhibitors that suppress inflammation have been studied as an anticancer treatment. Recently, many research groups have investigated the anti-angiogenic activity of natural compounds since some have been demonstrated to have anticancer properties. Among many natural compounds, we focused on betaine, which is known to suppress inflammation. Betaine, trimethylglycine (TMG), was first discovered in the juice of sugar beets and was later shown to be present in wheat, shellfish and spinach. In Southeast Asia, betaine is used in traditional oriental medicine for the treatment of hepatic disorders. Here, we report the anti-angiogenic action of betaine. Betaine inhibited in vitro angiogenic cascade, tube formation, migration and invasion of human umbilical vein endothelial cells (HUVECs). Betaine also inhibited in vivo angiogenesis in the mouse Matrigel plug assay. The mRNA expression levels of basic fibroblast growth factor (bFGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in HUVECs were decreased by betaine treatment. In addition, betaine suppressed NF-κB and Akt activation.

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1.	Folkman J and Shing Y: Angiogenesis. J Biol Chem. 267:10931–10934. 1992.
2.	Siddiqui FA, Desai H, Siddiqui TF and Francis JL: Hemoglobin induces the expression and secretion of vascular endothelial growth factor from human malignant cells. Hematol J. 3:264–270. 2002. View Article : Google Scholar : PubMed/NCBI
3.	Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
4.	Ferrara N and Kerbel RS: Angiogenesis as therapeutic target. Nature. 438:967–974. 2005. View Article : Google Scholar
5.	Isner JM and Asahara T: Angiogenesis and vasculogenesis as therapeutics strategies for postnatal neovascularization. J Clin Invest. 103:1231–1236. 1999. View Article : Google Scholar : PubMed/NCBI
6.	Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
7.	Balkwill F and Mantovani A: Inflammation and cancer: back to Virchow? Lancet. 357:539–545. 2001. View Article : Google Scholar : PubMed/NCBI
8.	Albini A, Tosetti F, Benelli R and Noonan DM: Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res. 65:10637–10641. 2005. View Article : Google Scholar : PubMed/NCBI
9.	Aggarwal BB, Shishodia S, Sandur SK, Pandey MK and Sethi G: Inflammation and cancer: how hot is the link? Biochem Pharmacol. 72:1605–1621. 2006. View Article : Google Scholar : PubMed/NCBI
10.	Sgambato A and Cittadini A: Inflammation and cancer: a multifaceted link. Eur Rev Med Pharmacol Sci. 14:263–268. 2010.
11.	Raman D, Sobolik-Delmaire T and Richmond A: Chemokines in health and disease. Exper Cell Res. 317:575–589. 2011. View Article : Google Scholar : PubMed/NCBI
12.	Rock GA and Dalgleish A: Infection, immunoregulation, and cancer. Immunol Rev. 240:141–159. 2011. View Article : Google Scholar
13.	Grivennikov SI and Karin M: Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev. 20:65–71. 2010. View Article : Google Scholar : PubMed/NCBI
14.	Yoshimura A: Signal transduction of inflammatory cytokines and tumor development. Cancer Sci. 97:439–447. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Karin M and Greteo FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005. View Article : Google Scholar : PubMed/NCBI
16.	Naldini A and Carraro F: Role of inflammatory mediators in angiogenesis. Curr Drug Targets Inflam Allergy. 4:3–8. 2005. View Article : Google Scholar
17.	da Rocha AB, Lopes RM and Schwartsmann G: Natural products in anticancer therapy. Curr Opin Pharmacol. 1:364–369. 2001.PubMed/NCBI
18.	Granci V, Dupertuis YM and Pichard C: Agiogenesis as a potential target of pharmaconutients in cancer therapy. Curr Opin Clin Nutr Metab Care. 13:417–422. 2010. View Article : Google Scholar : PubMed/NCBI
19.	Craig SA: Betaine in human nutrition. Am J Clin Nutr. 80:539–549. 2004.PubMed/NCBI
20.	Schrama JW, Heetkamp MJ, Simmins PH and Gerrits WJ: Dietary betaine supplementation affects energy metabolism of pigs. J Anim Sci. 81:1202–1209. 2003.PubMed/NCBI
21.	Holm PI, Ueland PM, Vollset SE, et al: Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler Thromb Vasc Biol. 25:379–385. 2005. View Article : Google Scholar : PubMed/NCBI
22.	Kim SK, Choi KH and Kim YC: Effect of acute betaine administration on hepatic metabolism of S-amino acids in rats and mice. Biochem Pharmacol. 65:1565–1574. 2003. View Article : Google Scholar : PubMed/NCBI
23.	Garcia-Perez A and Burg MB: Renal medullary organic osmolytes. Physiol Rev. 71:1081–1115. 1991.
24.	Sakamoto A and Murata N: Genetic engineering of glycine betaine synthesis in plants: current status and implications for enhancement of stress tolerance. J Exp Bot. 51:81–88. 2000. View Article : Google Scholar : PubMed/NCBI
25.	Steenge GR, Verhoef P and Katan MB: Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr. 133:1291–1295. 2003.PubMed/NCBI
26.	Go EK, Jung KJ, Kim JY, Yu BP and Chung HY: Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor-kappaB via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases. J Gerontol A Biol Sci Med Sci. 60:1252–1264. 2005. View Article : Google Scholar
27.	Dobrzanski P, Hunter K, Jones-Bolin S, et al: Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res. 64:910–919. 2004. View Article : Google Scholar : PubMed/NCBI
28.	Lin YG, Kunnumarkkara AB, Nair A, et al: Curcumin inhibits growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin Cancer Res. 13:3423–3430. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Szekanecz Z and Koch AE: Endothelial cells in inflammation and angiogenesis. Curr Drug Targets Inflamm Allergy. 4:319–323. 2005. View Article : Google Scholar : PubMed/NCBI
30.	Ono M: Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci. 99:1501–1506. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Jones KM, Wang H, Peskar BM, et al: Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanism and implications for cancer growth ulcer healing. Nat Med. 5:1418–1423. 1999. View Article : Google Scholar : PubMed/NCBI
32.	Cragg G and Suffness M: Metabolism of plant-derived anticancer agents. Pharmacol Ther. 37:425–461. 1988. View Article : Google Scholar : PubMed/NCBI
33.	Wani MC, Taylor HL, Wall ME, Coggon P and McPhail AT: Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 93:2325–2327. 1971. View Article : Google Scholar : PubMed/NCBI
34.	Nagy JA, Dvorak AM and Dvorak HF: EGF-A(164/165) and PIGF: roles in angiogenesis and arteriogenesis. Trends Cardiovasc Med. 13:169–175. 2003. View Article : Google Scholar : PubMed/NCBI
35.	Tsuda H, Ohshima Y, Nomoto H, et al: Cancer prevention by natural compounds. Drug Metab Pharmacokinet. 19:245–263. 2004. View Article : Google Scholar
36.	Parikh AA and Ellis LM: The vascular endothelial growth factor family and its receptors. Hematol Oncol Clin North Am. 18:951–971. 2004. View Article : Google Scholar : PubMed/NCBI
37.	Munoz-Chapuli R, Quesada AR and Angel Medina M: Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci. 61:2224–2243. 2004. View Article : Google Scholar : PubMed/NCBI
38.	Blavier L, Lazaryev A, Dorey F, Shackleford GM and DeClerck TA: Matrix metalloproteinases play an active role in Wnt1-induced mammary tumorigenesis. Cancer Res. 66:2691–2699. 2006. View Article : Google Scholar : PubMed/NCBI
39.	Bisacchi D, Benelli R, Venzetto C, Ferrari N, Tosetti F and Albini A: Anti-angiognesis and angioprevention: mechanisms, problems and perspectives. Cancer Detect Prev. 27:229–238. 2003. View Article : Google Scholar : PubMed/NCBI