title: Inhibitory effect of α-lipoic acid on thioacetamide-induced tumor promotion through suppression of inflammatory cell responses in a two-stage hepatocarcinogenesis model in rats.
abstract: To investigate the protective effect of α-lipoic acid (a-LA) on the hepatocarcinogenic process promoted by thioacetamide (TAA), we used a two-stage liver carcinogenesis model in N-diethylnitrosamine (DEN)-initiated and TAA-promoted rats. We examined the modifying effect of co-administered a-LA on the liver tissue environment surrounding preneoplastic hepatocellular lesions, with particular focus on hepatic macrophages and the mechanism behind the decrease in apoptosis of cells surrounding preneoplastic hepatocellular lesions during the early stages of hepatocellular tumor promotion. TAA increased the number and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of proliferating and apoptotic cells in the liver. Co-administration with a-LA suppressed these effects. TAA also increased the numbers of ED2(+), cyclooxygenase-2(+), and heme oxygenase-1(+) hepatic macrophages as well as the number of CD3(+) lymphocytes. These effects were also suppressed by a-LA. Transcript levels of some inflammation-related genes were upregulated by TAA and downregulated by a-LA in real-time RT-PCR analysis. Outside the GST-P(+) foci, a-LA reduced the numbers of apoptotic cells, active caspase-8(+) cells and death receptor (DR)-5(+) cells. These results suggest that hepatic macrophages producing proinflammatory factors may be activated in TAA-induced tumor promotion. a-LA may suppress tumor-promoting activity by suppressing the activation of these macrophages and the subsequent inflammatory responses. Furthermore, a-LA may suppress tumor-promoting activity by suppressing the DR5-mediated extrinsic pathway of apoptosis and the subsequent regeneration of liver cells outside GST-P(+) foci.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Fujii
authors.forename: Risa
authors.initials: R
authors.lastname: Segawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Liyun
authors.initials: L
authors.lastname: Wang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003043:Cocarcinogenesis; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013853:Thioacetamide / Q000037:antagonists & inhibitors / Q000633:toxicity; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018836:Inflammation Mediators; D017392:Thiobarbituric Acid Reactive Substances; D013853:Thioacetamide; D004052:Diethylnitrosamine; D008063:Thioctic Acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat; D003849:Deoxyguanosine
keywords: 8-OHdG; 8-hydroxydeoxyguanosine; Aldh1a1; Apoptosis; B-cell CLL/lymphoma 2; BNF; Bax; Bcl2; Bcl2-associated X protein; Bcl2-like 1; Bcl2l1; CMD; Casp; Cd4; Cd4 molecule; Cd8a; Cd8a molecule; Col1a1; Cox-2; Cu; Cx3cl1; Cxcl10; DAB; DEN; DR5; Death receptor 5 (DR5); EMIQ; Fadd; Fas (TNFRSF6)-associated via death domain; Fe; GST-P; Gpx2; Gstm1; HO-1; Hprt; Il1b; Il4; Inflammation; Liver tumor promotion; Mapk; Mmp; N-diethylnitrosamine; NAD(P)H dehydrogenase, quinone 1; Nfe2l2; Nqo1; PBS; PCNA; Ptgs2; ROS; Serpine1; TAA; TBARS; TRAIL; TUNEL; Tgfb2; Thioacetamide (TAA); Tnf; Tnfrsf10b; Tnfsf10; Txn1; a-LA; aldehyde dehydrogenase family 1 member A1; caspase; chemokine (C-X-C motif) ligand 10; chemokine (C-X3-C motif) ligand 1; choline-methionine-deficient diet; collagen, type I, alpha 1; copper; cyclooxygenase 2; death receptor 5; diaminobenzidine; enzymatically modified isoquercitrin; glutathione S-transferase mu 1; glutathione S-transferase placental form; glutathione peroxidase 2; heme oxygenase-1; hypoxanthine guanine phosphoribosyl transferase; interleukin 1 beta; interleukin 4; iron; matrix metalloproteinase; mitogen activated protein kinase; nuclear factor, erythroid derived 2, like 2; phosphate buffered solution; proliferating cell nuclear antigen; prostaglandin-endoperoxide synthase 2; reactive oxygen species; serine (or cysteine) peptidase inhibitor, clade E, member 1; terminal deoxynucleotidyl transferase-mediated nick end labeling; thioacetamide; thiobarbituric acid-reactive substances; thioredoxin 1; transforming growth factor, beta 2; tumor necrosis factor; tumor necrosis factor (ligand) superfamily, member 10; tumor necrosis factor receptor superfamily, member 10b; tumor necrosis factor-related apoptosis-inducing ligand; α-Lipoic acid (a-LA); α-lipoic acid; β-naphthoflavone