dinoprost and Cholangiocarcinoma

Chronic infection by the liver fluke Opisthorchis viverrini is a strong risk factor for cholangiocarcinoma. To clarify the involvement of oxidative stress and lipid peroxidation-derived DNA damage, etheno (epsilon)-DNA adducts (epsilondA, epsilondC) in WBC and plasma alpha-tocopherol were measured in samples collected from O. viverrini-infected Thai patients (n = 50) and healthy noninfected volunteers (n = 20). epsilondA and epsilondC levels were three to five times higher (P < 0.001) in infected patients than in controls; O. viverrini infection also increased two to three times in the plasma inflammatory indicators, 8-isoprostane, malondialdehyde, and nitrate/nitrite. Mean plasma alpha-tocopherol levels were two times lower in patients than in healthy controls (P < 0.001). Two months after a single dose to infected patients of the antiparasitic drug praziquantel, epsilondA and epsilondC levels in WBC were decreased to control level (P < 0.03); plasma 8-isoprostane, malondialdehyde, nitrate/nitrite, and alkaline phosphatase (ALP) were concomitantly lowered. epsilondA and epsilondC levels in WBC were positively correlated with plasma 8-isoprostane, malondialdehyde, and nitrate/nitrite levels and ALP activity, whereas plasma alpha-tocopherol levels showed inverse correlations. We conclude that chronic O.viverrini infection induces an accumulation of lipid peroxidation-derived DNA damage through oxidative/nitrative stress, which is lowered by the plasma alpha-tocopherol and by antiparasitic drug therapy. Etheno adducts in WBC and urine should be explored as a risk marker for opisthorchiasis-related cholangiocarcinoma, and to assess the efficacy of preventive and therapeutic interventions.

Topics: alpha-Tocopherol; Animals; Anthelmintics; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Dinoprost; DNA Adducts; Female; Humans; Leukocytes; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Nitrates; Nitrites; Opisthorchiasis; Opisthorchis; Oxidative Stress; Praziquantel

Cyclooxygenase 2 (COX-2) and cytosolic phospholipase A(2) (cPLA(2)) are the crucial rate-limiting enzymes in prostaglandin (PG) metabolism that show increased expression in a number of human cancers, including cholangiocarcinomas; and treatment of cholangiocarcinoma cell lines with COX-2 inhibitors can decrease proliferation. Cholangiocarcinomas also produce and proliferate in response to nonneoplastic biliary epithelial cell mitogens, such as interleukin 6 (IL-6) and hepatocyte growth factor (HGF). This study was designed to determine whether there is any relationship between eicosanoid metabolism and growth stimulation by IL-6 and HGF, two important biliary epithelial cell and cholangiocarcinoma mitogens. Incubation of SG231, a well-characterized human cholangiocarcinoma cell line, with HGF, IL-6, PGE(2), or PGF(2)alpha resulted in significantly increased cell growth. HGF and IL-6 also induced a rapid release of arachidonic acid (AA) from SG231 and increased the synthesis of PGE(2) and PGF(2)alpha. The cPLA(2) inhibitor arachidonyl fluorophosphonate (MAFP) and the COX-2 inhibitor NS-398 significantly inhibited HGF- and IL-6-induced release of AA, PG synthesis, and proliferation in SG231 cells as well as two other human cholangiocarcinoma cell lines, HuCCT1 and CC-LP-1 cells. Thus, PGs alone can induce cholangiocarcinoma growth, and the HGF- and IL-6-induced proliferation is mediated, at least in part, by PGs. HGF and IL-6 also induced a rapid phosphorylation of cPLA(2) (within 1 minute) but did not alter cPLA(2) and COX-2 protein expression. The HGF- and IL-6-induced cPLA(2) phosphorylation was blocked by the inhibitors of p38 and p42/44 MAP kinases, protein kinase C, calmodulin kinase, and tyrosine kinase, showing that HGF- and IL-6-induced AA release and PG production are mediated by phosphorylation of cPLA(2). In conclusion, molecular pathways link classic biliary epithelial cell mitogens to PG metabolism constituents in cholangiocarcinoma growth, which may be exploited as potential therapeutic targets.

Topics: Arachidonic Acids; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Division; Cholangiocarcinoma; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytosol; Dinoprost; Dinoprostone; Enzyme Inhibitors; Flavonoids; Hepatocyte Growth Factor; Humans; Imidazoles; Interleukin-6; Isoenzymes; Membrane Proteins; Mitogen-Activated Protein Kinases; Nitrobenzenes; Organophosphonates; Phospholipases A; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Pyridines; Sulfonamides; Tumor Cells, Cultured