By Lynn Keegan, RN, PhD, HNC, FAAN, and Gerald T. Keegan, MD, FACS
Part 1 of a 2-Part Series
Colorectal cancer is the third most common malignancy in the developed world. This cancer accounts for 60,000 deaths per year in the United States and 20,000 deaths per year in the United Kingdom. Although the incidence of the disease has appeared to drop slightly over just the past few years, the overall incidence and mortality of the disease, as well as the 50% five-year survival rate, has changed little over the past 40 years.1 Colon cancer affects almost equal proportions of men and women between ages 60 and 80.
The pathogenesis of colorectal cancer is believed to involve both genetic and environmental factors. The most important environmental factor is probably diet.2 Low-fiber diets have been associated with colon cancer. The effect of fiber has been controversial and some suggest that it is the effect of the phytoestrogens in fruit and vegetables rather than bulk alone that is preventive.3,4 Studies suggest an inverse relationship between colon cancer and dietary omega-3 fatty acids.5 The effects of smoking, lack of exercise, colorectal inflammation, and obesity also have been considered risk factors for colon cancer. A personal history of inflammatory bowel disease is a well-established risk factor for colorectal cancer.6 The presence of colonic polyps is also a concern. Polyps of the colon and rectum generally are benign, but may develop malignant degeneration and are considered precancerous.
Chemoprevention of Colon Cancer
Chemoprevention is defined as the use of pharmacologic interventions to stop the progression of normal cells to cancer cells. A number of agents—including aspirin, turmeric, and selenium—have been considered preventive for colon cancer. Additionally, there are ongoing studies on the effects of other non-steroidal anti-inflammatory agents (NSAIDs), vitamin D, and calcium as chemopreventive agents. This article will discuss data on turmeric and NSAIDs as chemopreventives. Next month, the chemopreventive effects of vitamin D and calcium will be examined.
Historical Use of Turmeric
Turmeric is a spice that comes from the root Curcuma longa and is a member of the Zingaberaceae (ginger) family. In Ayurveda, turmeric has been used for its medicinal properties and is administered topically, orally, and via inhalation.
Mechanism of Action
Role of inflammation. The modulation of the inflammatory cascade may be accomplished by a variety of means. Research is demonstrating that cancer initiation, promotion, progression, angiogenesis, and metastasis all may be related to inflammatory events. There is evidence linking emerging neoplasia and inflammatory eicosanoids (PGE2 and related prostaglandins). Although most research has emphasized the pharmaceutical applications of NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors, these agents fail to address alternate pathways available for the synthesis of proinflammatory eicosanoids. Evidence suggests the inhibition of lipoxygenase and its byproducts may be an overlooked but crucial component in complementary cancer therapies. Turmeric, as well as other selected nutritional and botanical agents—such as omega-3 fatty acids, antioxidants, boswellia, bromelain, and quercetin—may inhibit eicosanoid production and modulate both lipoxygenase and COX.7
Turmeric. Curcuminoids, which are components of turmeric, include mainly curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcumin.8 Turmeric is known to have a variety of pharmacologic effects, including antitumor, anti-inflammatory, anti-infectious, and perhaps immune-enhancing activities. The pleiotropic effects of turmeric are attributable at least in part to inhibition of transcriptional factors, as well as effects on other cytokines.9 Recently, turmeric has been demonstrated to possess anti-angiogenic effects and pro-apoptotic activities against tumor cell lines.10
Many investigators believe turmeric plays a role in prevention of colon cancer, but its mechanism of action is unclear. Studies have shown that treatment with turmeric can prevent and improve murine experimental colitis, a precursor of colon cancer. This finding suggests that turmeric could be a potential therapeutic agent for the treatment of patients with inflammatory bowel disease.9
Turmeric has long been known for its anti-inflammatory action.11 It may exert this activity by inhibition of a number of different molecules that play a role in inflammation.8 Turmeric has been demonstrated to suppress lipopolysaccharide-induced COX-2 expression in microglial cells.12
NSAIDs. Generalized colonic inflammation has been hypothesized to play a role in the pathogenesis of colon cancer. A recent prospective study involving more than 22,000 patients assessed the association of C-reactive protein (CRP) and the risk of colon and rectal cancers. CRP is an acute-phase protein produced in the liver in response to stimulation by interleukin-6 and is a non-specific measure of inflammatory disease. The results of this study showed an elevated plasma CRP concentration among persons who subsequently develop colon cancer. The data, although not separating the aspirin group of patients from the other NSAIDs patients, supported the concept that inflammation is a risk factor for the development of colon cancer in average-risk individuals.13 This article gives further support to considering the use of anti-inflammatory drugs in the chemoprevention of colon cancer.
NSAIDs, such as aspirin or ibuprofen, block COX-1 and COX-2 enzymes. Although COX-1 is necessary for healthy mucosal tissues, blood platelets, and kidneys, and COX-2 typically is produced by the body when there is inflammation, these substances also are produced by precancerous tissues such as colonic polyps. Aspirin has properties not shared by the COX-2 inhibitors and probably triggers its own set of endogenous anti-inflammatory mediators through its effect on vascular COX-2.14 Aspirin and the other NSAIDs may work by different mechanisms. A recent study suggested that selective COX-2 inhibition does not modify CRP levels,15 and suggested further that COX-2 inhibitors may not have a direct impact on CRP and could influence colon cancer by other, yet unknown mechanisms.16
Research Studies
Turmeric. Turmeric has been found to inhibit the growth of malignant cells both in vivo and in vitro. Studies on human tumor cell lines in India show that apoptosis was mediated through the generation of reactive oxygen species.17 A study comparing celecoxib with turmeric as well as several other agents was undertaken in five hereditary colorectal cell lines. The results of the study showed dose- and time-dependent antiproliferative activities by both celecoxib and turmeric. Celecoxib was the most effective antiproliferative agent, but turmeric displayed a more potent apoptosis-inducing activity.18
However, the anti-inflammatory effect of turmeric is only one of its pleiotropic effects on the prevention and perhaps treatment of colon cancer. One of the widely sought approaches is cancer chemoprevention that uses natural agents to reverse or inhibit the malignant transformation of colon cancer cells and to prevent invasion and metastasis. Turmeric possesses chemopreventive activity that works by targeting multiple signaling pathways such as the beta-catenin-mediated transactivation and cell-to-cell adhesion pathways in the prevention of colon cancer development.19 The apoptotic effect of turmeric in human cancer cells may be related to genetic up regulation at the level of "growth arrest and DNA damage inducible gene 153" messenger RNA transcription.20
Turmeric also has been found to protect DNA from damage from alkylating carcinogens in cultured Chinese hamster cells and is believed to be a chemopreventive agent by virtue of its ability to protect DNA as well as to induce DNA repair.21
The relationship between cytokines and turmeric has been investigated extensively. Cytokines are small proteins that have a specific effect on the interaction or communication between cells. Mitogen-activated protein kinase (MAPK) and NF-kappa B (NFkappaB) signaling cascades are thought to regulate apoptosis and cell survival. Turmeric is known to inhibit NFkappaB. Scientists in Ireland recently have studied turmeric effects upon MAPK signaling and apoptosis in human colon cancer cells and showed that c-jun N-terminal kinase played an important role in turmeric-mediated apoptosis in human colon cancer cells that may underlie its chemopreventive effects.22
NSAIDs. Epidemiologic studies have shown that people who regularly take NSAIDs to treat conditions such as arthritis have lower rates of colorectal polyps, colorectal cancer, and colorectal cancer deaths. Based on these promising epidemiologic data, as well as animal models treated with COX inhibitors, consideration has been given to these substances as chemopreventive. This concept has been reinforced further by the finding of human cancer tissue showing high levels of COX-2 expression.23 The recent characterization of COX-1 and COX-2 isoforms has led to an expanded understanding of how NSAIDs may help prevent polyp formation and subsequent malignant degeneration. COX enzymes are required for the conversion of arachidonic acid to prostaglandins. COX-2 mediates the inflammatory effects of COX activity. COX also is induced by a wide spectrum of growth factors and pro-inflammatory cytokines, and is as noted above23 over-expressed in numerous premalignant and malignant lesions.
Treatment with the selective COX-2 inhibitor celecoxib has shown promising results in the prevention of colorectal cancer. Numerous studies show that this selective COX-2 inhibitor is a potent suppressor of colon polyps both in animal models for familial adenomatous polyposis and in patients with this condition. This has led to the U.S. Food and Drug Administration approval of celecoxib for the treatment of patients with familial adenomatous polyposis where multiple polyps are present.24
The population-based Pharmacoepidemiologic Prescription Database of North Jutland County, Denmark, identified 113,538 persons who filled prescriptions for ibuprofen during 1989 through 1995 and determined subsequent mortality through 1996. Standardized mortality ratios (SMR) for 25 specific causes of death were computed compared with the general population. For colon cancer, SMRs were significantly below the standard three or more years after ibuprofen prescription. However, there was a nearly threefold increase in the number of deaths from gastrointestinal bleeding.25
Multiple studies—experimental, epidemiological, and randomized clinical trials (RCTs)—have provided evidence that aspirin and other NSAIDs can reduce the risk of colorectal adenoma and cancer.26-28 An extensive study of NSAIDs, colon cancer, and the possible involvement of an insulin-related pathway in more than 2,000 patients supported the protective effect of aspirin and NSAIDs on colorectal cancer risk. In addition, the observed interactions for aspirin/NSAIDs polymorphic genotypes suggest that mechanisms other than COX-2 inhibition may be contributing to the protective effect of aspirin and NSAIDs on colorectal cancer risk.29
Because of the gastrointestinal toxicity of aspirin and the non-selective NSAIDs, attention has been directed at the selective COX-2 inhibitors. These agents produce a decrease in the number and size of polyps in patients with familial adenomatous polyposis syndrome (FAP).30 A review of nine RCTs including more than 24,000 patients using aspirin, sulindac, and celecoxib showed substantial reduction, but not prevention, of precancerous colorectal adenomas in FAP.31 Prior studies using celecoxib and sulindac have been verified by these findings.32,33
Adverse Effects
Turmeric. No reported adverse effects of turmeric have been cited in the research literature.
NSAIDs. Gastrointestinal side effects associated with NSAID use are common. NSAID-associated dyspepsia occurs in up to 50% of patients who use these drugs, and heartburn, nausea, vomiting, and abdominal pain also can be observed. Nonselective NSAIDs predictably cause gastrointestinal mucosal injury because they inhibit production of prostaglandins in local tissue.34 This decline in prostaglandin production may disrupt the mucous layer and decrease secretion of bicarbonate, which can lead to back diffusion of hydrogen ions and damage to the mucosa.35 The major risk of aspirin and other NSAIDs is the possibility of bleeding secondary to their effects on platelet function. These effects can be particularly serious in the gastrointestinal tract where acute bleeding from ulcers and diverticular disease can be life-threatening and, as noted above in the Danish epidemiologic study, the death rate from gastrointestinal bleeding in patients on ibuprofen was three times that of the normal population.25
One case-controlled study found an association between the ingestion of NSAIDs and the development of severe diverticular complications including pericolic abscesses, generalized peritonitis, bleeding, and fistula formation.36 Selective inhibition of COX-2 by using COX-2 inhibitors allows for the beneficial effects of NSAIDs without adverse gastrointestinal results. COX-2 inhibitors are less likely to produce gastroscopically diagnosed ulcers but, as recent studies have shown, may increase the risk of myocardial infarction.37 Merck Pharmaceuticals voluntarily withdrew refecoxib from the market on Sept. 30, 2004. A patient taking refecoxib has a small absolute risk of a heart attack. The trial prompting Merck to pull the drug involved 2,600 patients, half of whom took 25 mg/d of the drug, and half of whom took a placebo. Among patients taking refecoxib for more than 18 months, there were 15 heart attacks or strokes for every 1,000 patients compared with 7.5 per 1,000 who were on placebo, essentially doubling the risk.
The gastric effects of the NSAIDs may be overcome by the concomitant use of H-2 blockers or proton pump inhibitors or a combination of these agents. Misoprostol, a synthetic prostaglandin analogue, also may decrease the risk of NSAID-induced gastrointestinal complications.38
Summary and Conclusion
In summary, population-based observational studies indicate that individuals had lower rates of colorectal cancer if they were taking various agents, including NSAIDs. In placebo-controlled trials in patients with familial adenomatous polyposis and in patients with sporadic colon adenomas, NSAIDs reduced the rates of adenomas. There is significant biologic rationale suggesting that these agents would be effective in reducing colorectal cancer as well.39
It is likely that routine use of turmeric may be helpful in prevention of inflammatory processes, which may give rise to or cause the progression of colon cancers. As yet, the literature is not definitive. However, there is certainly no harm in adding turmeric to the daily diet. Some of the ways include using curry sauces as well as adding turmeric to rice, soups, and stews.
Recommendation
People at high risk for colon cancer, but who have not had ulcer disease or gastrointestinal problems should consider the use of aspirin or non-specific NSAIDs. The concomitant use of H-2 blockers, proton pump inhibitors, and misoprostol can be considered gastrointestinal protectors. COX-2 inhibitors are less likely to produce gastrointestinal complications, but recently the increased incidence of myocardial infarction has been reported with refecoxib.
Gerald T. Keegan, MD, is Emeritus Staff, Scott & White Clinic and Hospital, and former Professor of Surgery (Urology), Texas A&M University School of Medicine.
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