title: Sub-chronic 90-day toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo.
abstract: Neamine, an inhibitor of angiogenin (ANG), is a new investigative anticancer drug currently in preclinical stage. Here we report the 90-day sub-chronic toxicity of neamine in SD rats and its anti-liver cancer activity in vitro and in vivo. Neamine has a No Observed Adverse Effect Level (NOAEL) of 12 and 16mg·kg-1·d-1for female and male rats, respectively. No mortality was found. The adverse effects included increased organ coefficients of spleen and kidney, increased BUN in both female and male rats at high dose, increased CR and decreased organ coefficients of heart and liver in male rats at high dose. All of which, except the kidney coefficient and BUN in males, returned to normal levels after 28-day recovery. Histopathological examination revealed vacuolar degeneration of glomerulus, degeneration of renal tubules and cast in the kidneys, which were also recovered except in males of high-dosing group. These results indicate that kidney is the most susceptible organ for neamine toxicity. Tissue microarray analysis validated that ANG is up-regulated in hepatocellular carcinoma accompanied by increased nuclear translocation, suggesting that ANG is a possible target for drug development in liver cancer treatment. Neamine blocked nuclear translocation of ANG in HUVEC and HepG2 cells, and inhibited ANG-stimulated cell proliferation without affecting basal level cell proliferation. Neamine also inhibited progression of HepG2 xenografts in athymic mice accompanied by decreased angiogenesis and cancer cell proliferation. These results suggest that neamine is a specific ANG inhibitor with low toxicity and high anti-liver cancer efficacy.
authors.affiliation: Department of pharmacology, School of Pharmacy, Huazhong University of Science and Technology, Wuhan 400030, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 400030, China.
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of pharmacology, School of Pharmacy, Huazhong University of Science and Technology, Wuhan 400030, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of hygienic toxicology, School of Public Health, Huazhong University of Science and Technology, Wuhan 400030, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of hygienic toxicology, School of Public Health, Huazhong University of Science and Technology, Wuhan 400030, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Shi
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Tufts University, Boston 02111, USA.
authors.forename: Guo-Fu
authors.initials: GF
authors.lastname: Hu
authors.affiliation: Department of pharmacology, School of Pharmacy, Huazhong University of Science and Technology, Wuhan 400030, China. Electronic address: wuyunxia@hust.edu.cn.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005601:Framycetin / Q000627:therapeutic use / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017207:Rats, Sprague-Dawley; D059550:Toxicity Tests, Subchronic
chemical_list: D000970:Antineoplastic Agents; D005601:Framycetin; C488396:neamine
keywords: Angiogenesis; Angiogenin; Liver cancer; Neamine; Sub-chronic toxicity