Increased expression of cyclooxygenase-2 protein during rat hepatocarcinogenesis caused by a choline-deficient, L-amino acid-defined diet and chemopreventive efficacy of a specific inhibitor, nimesulide

Abstract

Expression of cyclooxygenase (COX)-2 protein during rat hepatocarcinogenesis associated with fatty change, fibrosis, cirrhosis and oxidative DNA damage, caused by a choline-deficient, L-amino acid-defined (CDAA) diet were investigated in F344 male rats, along with the chemopreventive efficacy of the specific COX-2 inhibitor, nimesulide (NIM). Nimesulide, which was administered in the diet at concentrations of 200, 400, 600 and 800 p.p.m. for 12 weeks, decreased the number and size of preneoplastic enzyme-altered liver foci, levels of oxidative DNA damage, and the grade and incidence of fibrosis in a dose-dependent manner. A preliminary long-term study of 65 weeks also revealed that 800 p.p.m. NIM decreased the multiplicity of neoplastic nodules and hepatocellular carcinomas and prevented the development of cirrhosis. Western blot analysis revealed that COX-2 protein was barely expressed in control livers and increased approximately 2.9-fold in the livers of rats fed on a CDAA diet for 12 weeks and approximately 4.5-5.4-fold in tumors, with a diameter larger than 5 mm, at 80 weeks. Immunohistochemically, COX-2 protein was positive in sinusoidal and stromal cells in fibrotic septa, which were identified by immunoelectron microscopy as Kupffer cells, macrophages, either activated Ito cells or fibroblasts, after exposure to the CDAA diet for 12 weeks, whereas it was only occasionally weakly positive in sinusoidal, probably Kupffer, cells in control livers. In neoplastic nodules in rats fed on a CDAA diet for 30 and 80 weeks, sinusoidal cells and cells with relatively large round nuclei and scanty cytoplasm were strongly positive for COX-2 protein, with the neoplastic hepatocytes in the minority of the nodules, but not the cancer cells, being moderately positive. These results clearly indicate that rat hepatocarcinogenesis, along with fatty change, fibrosis and cirrhosis, is associated with increased expression of COX-2 protein, and point to the chemopreventive efficacy of a selective COX-2 inhibitor against, at least, the early stages of hepatocarcinogenesis.

Herpes simplex virus thymidine kinase gene transduction enhances tumor growth rate and cyclooxygenase-2 expression in murine colon cancer cells

“…In order to test this possibility, we monitored the growth rate of MC38 and MC38/HSV-tk tumors in mice treated with the selective COX-2 inhibitor, nimesulide, which has been previously demonstrated to exert antitumor activity. 50,51 In the current study, nimesulide treatment caused a significant inhibition in growth rate of both MC38 and MC38/HSV-tk tumors. However, nimesulide did not decrease the growth rate of MC38/HSV-tk tumors to a level similar to that of nimesulide-treated MC38 tumors (Fig 8).…”

“…[46][47][48] Moreover, selective COX-2 inhibitors have been reported to protect from tumorigenesis in vitro and in in vivo cancer models. [49][50][51] These pieces of evidence, as well as the established association of enhanced COX-2 expression with increased tumor growth, suggested that inhibition of PG synthesis would attenuate the enhancement of tumor growth rate that accompanies the presence of the HSV-tk gene. In order to test this possibility, we monitored the growth rate of MC38 and MC38/HSV-tk tumors in mice treated with the selective COX-2 inhibitor, nimesulide, which has been previously demonstrated to exert antitumor activity.…”

Mitochondrial DNA mutations in human cancer

“…Other defects in biochemical pathway include reduced pyruvate oxidation and increased lactic acid production (Lopez-Alarcon and Eboli, 1986;Mazurek et al, 1997;Eigenbrodt et al, 1998;Basso et al, 2004;Wenzel et al, 2005). Reduced fatty acid oxidation (Ockner et al, 1993;Hardy et al, 2003) increased glycerol production (Shaw and Wolfe, 1987;Beck and Tisdale, 2004) modified amino acid metabolism (Peluso et al, 2000;Denda et al, 2002;Maxwell and Rivera, 2003) and increased pentose phosphate pathway activity (Ferretti et al, 1993;Boros et al, 1998Boros et al, , 2000 are some common alterations associated with cancer cells. Mitochondrial mutations were also reported in normal subjects, especially with advancing age.…”

Nimesulide, a selective COX-2 inhibitor, acts synergistically with ionizing radiation against A549 human lung cancer cells through the activation of caspase-8 and caspase-3

“…It specifically inhibits the inducible form of COX, COX-2, rather than the constitutive form, COX-1 (12), and is well tolerated by adult, elderly, and pediatric patients (10). It also has chemopreventive activity against colon, liver, breast, tongue, and urinary bladder carcinogenesis (13)(14)(15)(16)(17) might be used as a radiosensitizer in the treatment of non-small cell lung cancer (18). However, the apoptotic characteristics of the combination of radiation and nimesulide remain to be elucidated.…”