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NS‐398, a selective cyclooxygenase 2 inhibitor, inhibited cell growth and induced cell cycle arrest in human hepatocellular carcinoma cell lines

Cyclooxygenase 2 (COX‐2) has been suggested to be associated with liver carcinogenesis. Several reports have shown that NSAIDs inhibit the growth of hepatocellular carcinoma cell lines. There is little evidence of how COX‐2 inhibitors regulate the proliferation of hepatocellular carcinoma cells or the mechanism involved. In our study, we investigated the growth‐inhibitory mechanism of a selective COX‐2 inhibitor, NS‐398, in 4 hepatocellular carcinoma cell lines by studying cell growth, COX‐2 and proliferating cell nuclear antigen (PCNA) expression, cell cycle distribution and the evidence of apoptosis. NS‐398 inhibited the growth of all 4 cell lines in a time‐ and dose‐dependent manner and the inhibitory effects were independent of the level of COX‐2 protein expression. PCNA expression was downregulated by NS‐398 in a dose‐independent manner. NS‐398 caused cell cycle arrest in the S phase with a reduction in cell numbers and cell accumulation in the G0/G1 phase, for all 4 cell lines. No evidence of apoptosis was observed in our present study. Our findings suggest that a selective COX‐2 inhibitor might serve as an effective tool for the chemoprevention and treatment of hepatocellular carcinomas. A reduction in cell number in the S phase may be an important event in cell cycle arrest caused by NS‐398 in hepatocellular carcinoma cell lines. © 2002 Wiley‐Liss, Inc.