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Introduction
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer worldwide and the third most common cause of cancer-related mortality (1). HCC usually occurs in the presence of continuous inflammation and hepatocyte regeneration during chronic hepatitis and cirrhosis; thus, mediators of inflammation are involved in the development of hepatic carcinogenesis (2). Drug treatment is the main therapy for patients in the advanced stages of disease. However, the response rate to traditional chemotherapy for HCC patients is far from satisfactory (3). Therefore, novel and effective pharmacological strategies are urgently required for the treatment of advanced HCC.
The non-steroidal anti-inflammatory drug celecoxib is a member of the cyclooxygenase-2 (COX-2) inhibitor drug family and is a potent and specific inhibitor of human COX-2 (4,5). The anticancer effects of celecoxib have been demonstrated in various different tumor types, including colorectal, lung, breast, prostate and head/neck cancer (6–8). The mechanism underlying the effects of celecoxib may be associated with COX-2-dependent or -independent pathways (9,10). A number of studies have investigated the mechanisms of the anticancer action of celecoxib. Celecoxib and derived compounds have been suggested to induce cell cycle arrest or apoptosis, inhibit tumor growth and suppress tumor neoangiogenesis (11). However, the mechanisms underlying celecoxib treatment of HCC are not yet completely understood.
In recent years, numerous advances in the understanding of HCC have been reported (12). The failure of transformed cells to undergo apoptosis markedly disrupts tissue homeostasis and allows proliferation of the resistant clone, a phenomenon frequently observed in HCC (13). Apoptosis is an evolutionarily conserved programmed mode of cell death and is critical for the sustained tissue homeostasis. Apoptosis signaling is tightly regulated by two main apoptotic pathways, termed the ‘extrinsic pathway’ and the ‘intrinsic pathway’. These pathways involve either cell surface death receptors, or the mitochondria and the endoplasmic reticulum, respectively (14,15). We have previously focused on the effects of celecoxib on the arachidonic acid (AA) signaling pathway in H22 mouse hepatoma cells. The imbalance between AA and prostaglandin (PG)E2, characterized by increased AA at a low dosage of celecoxib and reduced PGE2 at a high dosage of celecoxib, was demonstrated to be a significant indicator of celecoxib-mediated apoptosis in H22 cells (16). The present study was designed to clarify the targeting of the...