title: Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance.
abstract: Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI)>15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS)>110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aihara
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Douhara
authors.forename: Junichi
authors.initials: J
authors.lastname: Yamao
authors.forename: Masao
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Masahisa
authors.initials: M
authors.lastname: Toyohara
authors.forename: Akira
authors.initials: A
authors.lastname: Mitoro
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Sawai
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Chie
authors.initials: C
authors.lastname: Morioka
authors.forename: Masakazu
authors.initials: M
authors.lastname: Uejima
authors.forename: Masahito
authors.initials: M
authors.lastname: Uemura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000627:therapeutic use*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D018890:Chemoprevention / Q000379:methods; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000208:ethnology / Q000517:prevention & control*; D012709:Serum Albumin / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
chemical_list: D000597:Amino Acids, Branched-Chain; D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D001786:Blood Glucose; D012709:Serum Albumin; D042561:Vascular Endothelial Growth Factor B; D040301:Vascular Endothelial Growth Factor Receptor-2