Attenuation of insulin-resistance-based hepatocarcinogenesis and angiogenesis by combined treatment with branched-chain amino acids and angiotensin-converting enzyme inhibitor in obese diabetic rats
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Because neovascularization plays an important role in HCC, including hepatocarcinogenesis, an angiostatic therapy would be a promising approach for chemoprevention against HCC. The aim of the present study was to examine the combined effect of clinically used branched-chain amino acids (BCAAs) and an angiotensin-converting enzyme inhibitor (ACE-I), in conjunction with neovascularization, on hepatocarcinogenesis under the condition of IR.
The combined effect of the treatment on the development of liver enzyme-altered preneoplastic lesions, angiogenesis, and several indices was elucidated in obese diabetic rats. We also performed several sets of in vitro experiments to examine the mechanisms involved.
When used individually, both BCAAs and ACE-I at clinically comparable low doses significantly attenuated the development of preneoplastic lesions, along with the suppression of both angiogenesis and vascular endothelial growth factor (VEGF) expression. The combination treatment with both agents exerted a more potent inhibitory effect than that of either single agent. Our in vitro study showed a similar combined effect on endothelial cell tubule formation.
This combination regimen showed a marked chemopreventive effect against hepatocarcinogenesis, along with suppression of neovascularization and VEGF expression, in obese diabetic rats. Because both BCAAs and ACE-Is are widely used in clinical practice, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC in the future.
- Kaji K, Yoshiji H, Kitade M, Ikenaka Y, Noguchi R, Yoshii J, et al. Impact of insulin resistance on the progression of chronic liver diseases. Int J Mol Med. 2008;22:801–8.
- Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48(Suppl 1):S20–37. CrossRef
- Kahn CR. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism. 1978;27:1893–902. CrossRef
- Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 2005;54:533–9. CrossRef
- El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126:460–8. CrossRef
- Mise M, Arii S, Higashituji H, Furutani M, Niwano M, Harada T, et al. Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology. 1996;23:455–64. CrossRef
- Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology. 1998;28:68–77. CrossRef
- Yoshiji H, Kuriyama S, Hicklin DJ, Huber J, Yoshii J, Miyamoto Y, et al. KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells. Hepatology. 1999;30:1179–86. CrossRef
- Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatology. 2004;39:1517–24. CrossRef
- Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039–49. CrossRef
- Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109. CrossRef
- Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90. CrossRef
- Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006;42:3127–39. CrossRef
- Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7:475–85. CrossRef
- Berenson A. A cancer drug shows promise, at a price that many can’t pay. NY Times (Print). 2006;A1:C2.
- Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124:1792–801. CrossRef
- Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol. 2005;3:705–13. CrossRef
- Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res. 2006;35:204–14.
- Yoshiji H, Noguchi R, Kitade M, Kaji K, Ikenaka Y, Namisaki T, et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol. 2009;44:483–91. CrossRef
- Kerbel RS. Clinical trials of antiangiogenic drugs: opportunities, problems, and assessment of initial results. J Clin Oncol. 2001;19:45S–51S.
- Yoshiji H, Kuriyama S, Noguchi R, Fukui H. Angiotensin-I converting enzyme inhibitors as potential anti-angiogenic agents for cancer therapy. Curr Cancer Drug Targets. 2004;4:555–67. CrossRef
- Yoshiji H, Noguchi R, Ikenaka Y, Kitade M, Kaji K, Tsujimoto T, et al. Renin-angiotensin system inhibitors as therapeutic alternatives in the treatment of chronic liver diseases. Curr Med Chem. 2007;14:2749–54. CrossRef
- Sato T, Asahi Y, Toide K, Nakayama N. Insulin resistance in skeletal muscle of the male Otsuka Long-Evans Tokushima fatty rat, a new model of NIDDM. Diabetologia. 1995;38:1033–41. CrossRef
- Yoshiji H, Kuriyama S, Kawata M, Yoshii J, Ikenaka Y, Noguchi R, et al. The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res. 2001;7:1073–8.
- Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, et al. Combination of vitamin K(2) and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression. J Hepatol. 2005;42:687–93. CrossRef
- Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology. 2002;35:834–42. CrossRef
- Saito M, Hamasaki M, Shibuya M. Induction of tube formation by angiopoietin-1 in endothelial cell/fibroblast co-culture is dependent on endogenous VEGF. Cancer Sci. 2003;94:782–90. CrossRef
- Kitade M, Yoshiji H, Kojima H, Ikenaka Y, Noguchi R, Kaji K, et al. Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology. 2006;44:983–91. CrossRef
- Saif MW. Anti-angiogenesis therapy in pancreatic carcinoma. JOP. 2006;7:163–73.
- Scappaticci FA, Smith R, Pathak A, Schloss D, Lum B, Cao Y, et al. Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice. Mol Ther. 2001;3:186–96. CrossRef
- Yoshiji H, Noguchi R, Toyohara M, Ikenaka Y, Kitade M, Kaji K, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol. 2009;51:315–21. CrossRef
- Tsuchiya K, Asahina Y, Sato T, Tanaka I, Hirayama Y, Yasui N et al. Oral supplementation with branched-chain amino acid (BCAA) improves survival and decreases the third time recurrence after successful treatment of hepatocellular carcinoma (HCC). J Hepatol (EASL proceeding) 2009; 48 suppl No2:S160
- Shibuya M. Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct Funct. 2001;26:25–35. CrossRef
- Ferrara N. VEGF: an update on biological and therapeutic aspects. Curr Opin Biotechnol. 2000;11:617–24. CrossRef
- Yoshiji H, Yoshii J, Ikenaka Y, Noguchi R, Tsujinoue H, Nakatani T, et al. Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats. J Hepatol. 2002;37:22–30. CrossRef
- Sanchez-Lopez E, Lopez AF, Esteban V, Yague S, Egido J, Ruiz-Ortega M, et al. Angiotensin II regulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha induction and redox mechanisms in the kidney. Antioxid Redox Signal. 2005;7:1275–84. CrossRef
- Murata K, Moriyama M. Isoleucine, an essential amino acid, prevents liver metastases of colon cancer by antiangiogenesis. Cancer Res. 2007;67:3263–8. CrossRef
- Li CY, Shan S, Huang Q, Braun RD, Lanzen J, Hu K, et al. Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst. 2000;92:143–7. CrossRef
- Frachon S, Gouysse G, Dumortier J, Couvelard A, Nejjari M, Mion F, et al. Endothelial cell marker expression in dysplastic lesions of the liver: an immunohistochemical study. J Hepatol. 2001;34:850–7. CrossRef
- Nishitani S, Ijichi C, Takehana K, Fujitani S, Sonaka I. Pharmacological activities of branched-chain amino acids: specificity of tissue and signal transduction. Biochem Biophys Res Commun. 2004;313:387–9. CrossRef
- Nishitani S, Takehana K, Fujitani S, Sonaka I. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1292–300. CrossRef
- Kawaguchi T, Taniguchi E, Itou M, Sumie S, Oriishi T, Matsuoka H, et al. Branched-chain amino acids improve insulin resistance in patients with hepatitis C virus-related liver disease: report of two cases. Liver Int. 2007;27:1287–92.
- Kawaguchi T, Nagao Y, Matsuoka H, Ide T, Sata M. Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int J Mol Med. 2008;22:105–12.
- Yoshiji H, Kuriyama S, Fukui H. Angiotensin-I-converting enzyme inhibitors may be an alternative anti-angiogenic strategy in the treatment of liver fibrosis and hepatocellular carcinoma. Possible role of vascular endothelial growth factor. Tumour Biol. 2002;23:348–56. CrossRef
- Attenuation of insulin-resistance-based hepatocarcinogenesis and angiogenesis by combined treatment with branched-chain amino acids and angiotensin-converting enzyme inhibitor in obese diabetic rats
Journal of Gastroenterology
Volume 45, Issue 4 , pp 443-450
- Cover Date
- Print ISSN
- Online ISSN
- Springer Japan
- Additional Links
- Angiotensin-converting enzyme
- Branched-chain amino acid
- Hepatocellular carcinoma
- Insulin resistance
- Vascular endothelial growth factor
- Industry Sectors
- Author Affiliations
- 1. Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan