Targeting beta-catenin by celecoxib (Celebrex) as an anti-cancer mechanism of action and as a lead for the identification of improved oncology agents
SummaryDespite the cardiovascular risks that have recently emerged following prolonged treatment with COX-2 inhibitors, this class of drug continues to receive interest as an approach to chemoprevention. Celebrex, which was approved in 1998 for the treatment of familial adenomatous polyposis (FAP) has been shown to reduce the development of precancerous colorectal polyps by 28%. Data recently highlighted in the FASEB journal suggests that at least part of the efficacy of celebrex may be related to the
Until preventative and diagnostic approaches to cancer are significantly improved patients will continue to present to clinicians with tumors that have progressed to a stage where metastasis will in many cases be inevitable. This is particularly the case for the 160,000 patients seen yearly in the United States with colon cancer. Late presentation means that as many as 40-50% of patients presenting with colorectal cancer develop metastatic liver cancer; metastatic progression to other sites including bone and the brain is also common. The treatment of advanced disease is clinically challenging however the introduction of two innovative agents in early 2004, Genentech/Roche's Avastin (bevacizumab) and BMS/Merck KGaA/ImClone's Erbitux (cetuximab), is expected to significantly alter the treatment landscape for colorectal cancer (see Colorectal Cancer - Avastin and Erbitux Pave The Way For Pipeline Targeted Therapies). Simultaneously various chemopreventative strategies are being evaluated in the field of colorectal cancer.
Several lines of evidence suggest that the cyclooxygenase enzymes (specifically COX-2) might be an important molecular target for the intervention of cancer at both early and late stages of some cancers, providing an opportunity for both cancer prevention and therapy. For example approximately 80% of all colorectal tumors have been shown to overexpress COX-2, and the subsequent increase in prostaglandin levels has been shown to promote cell proliferation, angiogenesis and metastasis. The chemopreventive efficacy of NSAIDs against colorectal cancer has been established. Also, NSAIDs may decrease the incidence of carcinomas of the esophagus, stomach, breast, lung, prostate, urinary bladder and ovary.The COX-2 inhibitor celebrex has been evaluated in patients with familial adenomatous polyposis (FAP), a genetic condition that often leads to colorectal cancer. The number of colorectal polyps in these patients was reduced by 28% leading to Pfizer's celecoxib (celebrex) being approved by the FDA in 1999 for the treatment of this condition. Currently, celecoxib is the only NSAID, which was approved by the FDA and EMEA for the treatment of these FAP patients
APPROVe (Adenomatous Polyp Prevention on Vioxx) was a similar trial designed to evaluate the efficacy of Merck's Vioxx (rofecoxib) however the study instead revealed an increased relative risk for confirmed cardiovascular events, beginning after 18 months of treatment in the patients taking Vioxx compared to those taking placebo. More recently Solomon et al (2005) reported that death from cardiovascular causes occurred in 2.3% of patients at risk of colorectal cancer administered 200 mg of celecoxib twice daily compared to 1% of individuals receiving placebo. The incidence of death rose further to 3.4% in patients receiving 400 mg of celecoxib twice daily.
These data sparked major upheaval with the pharmaceutical sector as Vioxx was withdrawn and other COX-2 inhibitors were subject to the scrutiny of regulatory bodies and the legal profession. In April, 2005, the FDA announced that sales of Celebrex could continue but must be accompanied by modified labelling acknowledging emergent cardiovascular (as well as gastrointestinal and cutaneous) safety data. Recent regulatory statements have also opened the door to possible reintroduction of Vioxx in the future.While the future of the COX-2 class is unfolding, studies are being conducted to establish the mechanism by which this class exerts its cancer preventive activity.
Beta-catenin expression is regulated by the adenomatous polyposis coli (APC) signaling pathway and mutations in the APC-gene contributes to FAP. Sporadic colorectal cancer is considerably more common than FAP and reports that APC-gene mutations are found in ~80% of all sporadic colon cancer diseases enhances the potential of this pathway as a therapeutic target. As a consequence of APC-mutation, nearly all colon carcinoma tissues show significant overexpression of beta-catenin, which has been attributed to be crucial for the early stages of colorectal carcinogenesis. Beta-catenin contributes to cell attachment and also the expression of proteins involved in tumor development. Normally beta-catenin is regulated by phophorylation, and particularly by glycogen synthase kinase-3 beta, which in turn controls its ubiquitination and degradation; defects in this process result in nuclear translocation which in turn causes the overexpression of various proteins including COX-2. Recent studies have suggested that celecoxib has an antitumorigenic effect which is independent of direct COX-2-inhibition.
In the highlighted FASEB study Maier et al investigate the possibility that celecoxib prevents colorectal tumor progression by targeting the beta-catenin/adenomatous polyposis coli (APC) signaling pathway. Maier et al report that following a transient increase in protein levels, celecoxib produces a near total block of beta-catenin levels and nuclear translocation in caco-2 cells. The initial increase in cytoplasmic beta-catenin appeared to result from a redistribution of protein attached to the outer cell membrane and did not appear to result in increased DNA binding. Delayed reduction in protein levels was related to increased ubiquitination and degradation through the proteasomal pathway. This redistribution and eventual degradation of beta-catenin was under the apparent control of glycogen synthase kinase-3 beta activity. The authors speculate that celecoxib acts by inhibiting PDK-1, which results in inactivation of Akt kinase and in subsequent activation of glycogen synthase kinase-3 beta. In addition to this mechanism, celecoxib also increases caspase-3 which can degrade beta-catenin as well as increase apoptosis. The effect of celecoxib on beta-catenin was also seen, albeit to a lesser extent, in prostate and breast cancer cell lines. Likewise the effect was quite selective for celecoxib with rofecoxib and flurbiprofen both having little effect on beta-catenin.
The present study suggests that at least in colorectal cancer, the anticancer activity of celecoxib may result from the degradation of beta-catenin rather than from an inhibition of COX-2 activity. These data are highly important since COX-2 inhibition has been associated with cardiovascular risk. Although COX-2 inhibition does appear to produce anti-cancer activity, the modelling of celocoxib analogues with reduced COX-2 inhibitory activity but which optimally cause the degradation of beta-catenin may retain the therapeutic efficacy of celocoxib but with minimal cardiovascular risk. This may be particularly true in colorectal cancer since strong nuclear or cytoplasmatic beta-catenin staining in colorectal cancer tissues correlates with more invasive tumor growth, a higher susceptibility of disease recurrence after surgery, and a lower survival rate.
Although oncogenic mutations of beta-catenin have only been discovered in a small fraction of non-colon cancers, elevated levels of beta-catenin protein have been observed in most common forms of human malignancies, indicating that activation of this pathway may play an important role in tumor development and that molecules able to reduce beta-catenin levels may be of general use in the treatment of cancer.
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