Isoleucine, an essential amino acid, prevents liver metastases of colon cancer by antiangiogenesis.
In spite of recent advances in the treatment of colon cancer, multiple liver metastases of colon cancer are still difficult to treat. Some chemotherapeutic regimens have been reported to be efficient, but there is a high risk of side effects associated with these. Here, we show that isoleucine, an essential amino acid, prevents liver metastases in a mouse colon cancer metastatic model. Because isoleucine is a strong inducer of beta-defensin, we first hypothesized that it prevented liver metastases via the accumulation of dendritic cells or memory T cells through up-regulation of beta-defensin. However, neither beta-defensin nor immunologic responses were induced by isoleucine in both mouse livers and spleens. Furthermore, isoleucine prevented liver metastasis in nude mice, which lack T cells and natural killer T cells. Finally, we discovered a novel mechanism of isoleucine: down-regulation of angiogenesis via inhibition of vascular endothelial growth factor, partially through the mammalian target of the rapamycin pathway, independent of hypoxia-inducible factor 1-alpha. Importantly, isoleucine is safe for administration to humans because it does not affect cell viability. Isoleucine could be a novel prophylactic drug for the prevention of liver metastases of colon cancer.
Murata
Kazumoto
K
The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie, Japan.
Moriyama
Masami
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007532:Isoleucine / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000276:immunology; D008113:Liver Neoplasms / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
D020533:Angiogenesis Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D007532:Isoleucine; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases