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.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Noguchi
Ryuichi
R
Kaji
Kosuke
K
Ikenaka
Yasuhide
Y
Shirai
Yusaku
Y
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Tsujimoto
Tatsuhiro
T
Kawaratani
Hideto
H
Fukui
Hiroshi
H
D000597:Amino Acids, Branched-Chain / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D007333:Insulin Resistance; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000517:prevention & control; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000209:etiology; D009765:Obesity / Q000150:complications; D051381:Rats; D020334:Rats, Inbred OLETF; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000597:Amino Acids, Branched-Chain; D000806:Angiotensin-Converting Enzyme Inhibitors; D042461:Vascular Endothelial Growth Factor A