Lipid Peroxidation and Cyclooxygenase-2 Activity in Human Hepatocellular Carcinoma Cell Lines With and Without Multiple Drug Resistance: Correlation With Cell Growth

摘要

Intrinsic or acquired resistance to antineoplastic drugs is the main cause of failure in cancer chemotherapy. Human hepatocellular carcinoma (HCC) has been increasing on a worldwide scale and it is among the most chemoresistant tumors. One of the main mechanisms of drug resistance is related to the over-expression of the gene that encodes a transmembrane P-glycoprotein which is involved in drug extrusion from the cells that possess the multiple drug-resistant (MDR1) phenotype [1]. Cancers with an MDR phenotype are more resistant to several anticancer drugs. Free radical formation is purported to be involved in cytotoxic effects of anticancer agents. However in HCC cells the expression of MDR1 phenotypeper se does not increase significantly the resistance to iron-stimulated lipid peroxidation [2]. Moreover hepatitis B and C viruses are found to be important factors of hepatocarcinogenesis, through the induction of cell proliferation and angiogenesis. Cyclooxygenase-2 (COX-2) has now been identified as expressed in a number of cancers, including HCC [3], but whether COX-2 activity affects cell growth and susceptibility to free radical attack in human HCC cell lines has not been elucidated. To assess these points, an HCC MDR1 cell line highly resistant to doxorubicin, Pl(0.5), and the parental drug-sensitive cells, P5, were studied for their susceptibility to lipid peroxidation and for the effect afforded by nimesulide, a COX-2 inhibitor.