Cyclooxygenases in hepatocellular carcinoma

Abstract

M a n y e p i d e m i o l o g i c a l s t u d i e s d e m o n s t r a t e t h a t treatment with non-steroidal anti-inflammatory drugs(NSAIDs) reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase (COX) enzymes are well-known targets of NSAIDs. However, conventional NSAIDs nonselectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by proinflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, m a l i g n a n t , a n d m e t a s t a s t i c c a n c e r s , i n c l u d i n g hepatocellular carcinoma (HCC). Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated H C C s o r h i s t o l o g i c a l l y n o r m a l l i v e r , s u g g e s t i n g that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC.In tumors, overexpression of COX-2 leads to an increase in prostaglandin (PG) levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells.The availability of novel agents that selectively inhibit COX-2 (COXIB), has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood.Increasing evidence suggests the involvement of molecular targets other than COX-2 in the antiproliferative effects of COX-2 selective inhibitors. Therefore, COX-inhibitors may use both COX-2-dependent and COX-2-independent mechanisms to mediate their antitumor properties, although their relative contributions toward the in vivo effects remain less clear.Here we review the features of COX enzymes, t h e r o l e o f t h e e x p r e s s i o n o f C O X i s o f o r m s i n hepatocarcinogenesis and the mechanisms by which they may contribute to HCC growth, the pharmacological properties of COX-2 selective inhibitors, the antitumor effects of COX inhibitors, and the rationale and feasibility of COX-2 inhibitors for the treatment of HCC.

A Cyclooxygenase-2/Prostaglandin E2 Pathway Augments Activation-Induced Cytosine Deaminase Expression within Replicating Human B Cells

“…This possibility was heightened by recent reports that AID is atypically expressed within several nonlymphoid tissues characterized by significant inflammation and high COX-2 expression, for example, Helicobacter pylori-infected gastric epithelium, normal hepatocytes adjacent to hepatocarcinoma, and inflamed biliary tract epithelium (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Importantly, in some of the above tissues, AID appeared to be functionally active and linked to mutations in the protooncogenes, p53 or c-Myc (16,19,20,27).…”

107 a Randomised Controlled Trial of Meloxicam, a Cox-2 Inhibitor, to Prevent Hepatocellular Carcinoma Recurrence After Initial Curative Treatment

“…The number of patients at risk at each time point is shown below the graphs between Cox-2 expression and carcinogenesis of HCC has been reported in many basic and clinical studies [21,22]. Selective inhibition of Cox-2 is also expected to show activity for cancer prevention [16,23]. The Cox-2 level in non-cancerous lesions increased from normal liver to chronic hepatitis to cirrhosis, and such expression of Cox-2 may be involved in the postoperative recurrence of HCC [24].…”

Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and β-naphthoflavone

“…COX-2 may be involved in the early stage of hepatocarcinogenesis, and the increased expression of COX-2 in noncancerous liver tissues has been significantly associated with shorter disease-free survival in patients with hepatocellular carcinomas (Cervello and Montalto, 2006). In tumors in human, overexpression of COX-2 leads to an increase in prostaglandin (PG) levels which affects many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, and stimulation of cell growth, as well as invasiveness and the metastatic potential of tumor cells (Cervello and Montalto, 2006). Several reports suggest that OPZ might have an anti-inflammation effect (Kedika et al, 2009;Shivanna et al, 2011).…”