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.
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.
['Fujii|Yuta|Y|', 'Segawa|Risa|R|', 'Kimura|Masayuki|M|', 'Wang|Liyun|L|', 'Ishii|Yuji|Y|', 'Yamamoto|Ryuichi|R|', 'Morita|Reiko|R|', 'Mitsumori|Kunitoshi|K|', 'Shibutani|Makoto|M|']
D000080242:8-Hydroxy-2'-Deoxyguanosine D000818:Animals D016588:Anticarcinogenic Agents D017209:Apoptosis D002273:Carcinogens D003043:Cocarcinogenesis D003849:Deoxyguanosine D004052:Diethylnitrosamine D051549:Glutathione S-Transferase pi D018836:Inflammation Mediators D008099:Liver D008114:Liver Neoplasms, Experimental D008264:Macrophages D008297:Male D051381:Rats D011916:Rats, Inbred F344 D013853:Thioacetamide D017392:Thiobarbituric Acid Reactive Substances D008063:Thioctic Acid
α-lipoic acid α-Lipoic acid (a-LA) a-LA Thioacetamide (TAA) thioacetamide TAA N-diethylnitrosamine Apoptosis glutathione S-transferase placental form 8-OHdG 8-hydroxydeoxyguanosine Aldh1a1 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 NAD(P)H dehydrogenase, quinone 1 Nfe2l2 Nqo1 PBS PCNA Ptgs2 ROS Serpine1 TBARS TRAIL TUNEL Tgfb2 Tnf Tnfrsf10b Tnfsf10 Txn1 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 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 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 β-naphthoflavone