Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 28, 2006; 12(32): 5113-5121
Published online Aug 28, 2006. doi: 10.3748/wjg.v12.i32.5113
Cyclooxygenases in hepatocellular carcinoma
Melchiorre Cervello, Giuseppe Montalto
Melchiorre Cervello, Institute of Biomedicine and Molecular Immunology “Alberto Monroy”, National Research Council, Palermo, Italy
Giuseppe Montalto, Department of Clinical Medicine, University of Palermo, Palermo, Italy
Author contributions: All authors contributed equally to the work.
Supported by a grant from the Associazione Italiana per la Ricerca sul Cancro and from the Italian Ministero dell’Università e della Ricerca Scientifica (ex 60%, year 2003)
Correspondence to: Melchiorre Cervello, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, C.N.R., Via Ugo La Malfa 153, Palermo 90146, Italy. cervello@ibim.cnr.it
Telephone: +39-91-6809534 Fax: +39-91-6809548
Received: December 3, 2005
Revised: January 10, 2006
Accepted: January 14, 2006
Published online: August 28, 2006

Many epidemiological studies demonstrate that 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 non-selectively 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 pro-inflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma (HCC). Overexpression of COX-2 in patients with HCC is generally higher in well-differentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting 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 anti-proliferative 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, the role of the expression of COX isoforms in 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.

Keywords: Cyclooxygenase-2, Cyclooxygenase-1, Hepatocellular carcinoma, Non-steroidal anti-inflammatory drugs, Inhibit cyclooxygenase-2