Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398, a selective COX-2 inhibitor.
Hepatocellular carcinoma (HCC) is a growing human health problem worldwide. Limited treatment and poor prognosis of this disease emphasize the importance in developing an effective chemoprevention. Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Although COX-2 inhibitors have been tested for chemoprevention of colon cancer, it remains unknown whether these agents possess anti-HCC effects as well. The present study assessed the effects of a selective COX-2 inhibitor, NS-398, on proliferation of human hepatoma cells in association with COX-2 expression, and the possible mechanisms. In four tested human hepatoma cell lines, overexpression of COX-2 was confirmed in HepG2, HuH7, and Chang liver cells, but not in PLC/PRF/5 cells. Addition of 50 micro M NS-398 resulted in both dose-dependent and time-course inhibition of HepG2 proliferation. In contrast, addition of 50 micro M NS-398 to COX-2 non-expressing PLC/PRF/5 cells resulted in only a mild reduction of cell proliferation. Consistent with this, a 48-h culture of HepG2 cells with 50 micro M NS-398 caused a significant decrease of prostaglandin E2 (PGE2) production. While, the same NS-398 treatment showed only a mild suppression of PGE2 production in COX-2 non-expressing PLC/PRF/5 cells. These findings indicate that NS-398-induced suppression of HepG2 proliferation appears mediated by decreased COX-2/prostaglandin (PG) production. We also found that NS-398-induced inhibition of HepG2 proliferation was associated with decreased 5-bromo-2'-deoxyuridine (BrdU) uptake, suggesting a reduced cell cycle progression in G1-S transition. NS-398 treatment also enhanced the apoptotic rate in COX-2 expressing HepG2 cells, but not in COX-2 non-expressing PLC/PRF/5 cells. Our findings confirmed an effective inhibitory effect of NS-398 on proliferation of COX-2 expressing human hepatoma cells through a decreased COX-2/PG activity that is associated with altered cell cycle progression and apoptotic rate.
Hu
Ke-Qin
KQ
Loma Linda University Medical Center, Loma Linda, CA 92354, USA. khu@ahs.llumc.edu
Yu
Chang-Hong
CH
Mineyama
Yoshimitsu
Y
McCracken
John D
JD
Hillebrand
Donald J
DJ
Hasan
Mateen
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001973:Bromodeoxyuridine; D015232:Dinoprostone