Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.

Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation.

Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents. NSAIDs restore normal apoptosis in human adenomatous colorectal polyps and in various cancer cell lines that have lost adenomatous polyposis coli gene function. NSAIDs also inhibit angiogenesis in cell culture and rodent models of angiogenesis. Many epidemiologic studies have found that long-term use of NSAIDs is associated with a lower risk of colorectal cancer, adenomatous polyps, and, to some extent, other cancers. Two NSAIDs, sulindac and celecoxib, have been found to inhibit the growth of adenomatous polyps and cause regression of existing polyps in randomized trials of patients with familial adenomatous polyposis (FAP). However, unresolved questions about the safety, efficacy, optimal treatment regimen, and mechanism of action of NSAIDs currently limit their clinical application to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective drugs for chemoprevention is complicated by the potential of even rare, serious toxicity to offset the benefit of treatment, particularly when the drug is administered to healthy people who have low annual risk of developing the disease for which treatment is intended. This review considers generic approaches to improve the balance between benefits and risks associated with the use of NSAIDs in chemoprevention. We critically examine the published experimental, clinical, and epidemiologic literature on NSAIDs and cancer, especially that regarding colorectal cancer, and identify strategies to overcome the various logistic and scientific barriers that impede clinical trials of NSAIDs for cancer prevention. Finally, we suggest research opportunities that may help to accelerate the future clinical application of NSAIDs for cancer prevention or treatment.

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Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues

Overexpression of Cyclooxygenase-2 Is Sufficient to Induce Tumorigenesis in Transgenic Mice

New data indicate that primary dysfunction in the tumour microenvironment, in addition to epithelial dysfunction, can be crucial for carcinogenesis. These recent findings make a compelling case for targeting the microenvironment for cancer chemoprevention. We review new insights into the pathophysiology of the microenvironment and new approaches to control it with chemopreventive agents. The microenvironment of a cancer is an integral part of its anatomy and physiology, and functionally, one cannot totally dissociate this microenvironment from what have traditionally been called 'cancer cells'. Finally, we make suggestions for more effective clinical implementation of this knowledge in preventive strategies.

The tumour microenvironment as a target for chemoprevention

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been observed to reduce the relative risk of breast cancer. This prompted our investigation of the chemopreventive potential of celecoxib, a specific cyclooxygenase 2 blocker, against mammary carcinogenesis induced by 7,12-dimethyl-benz(a)anthracene in female Sprague Dawley rats. Treatment with celecoxib was examined and compared to treatment with the general NSAID, ibuprofen, and to a control group receiving only dimethylbenz(a)anthracene. Dietary administration of celecoxib (1500 ppm) produced striking reductions in the incidence, multiplicity, and volume of breast tumors relative to the control group (68%, 86%, and 81%, respectively; P < 0.001). Ibuprofen also produced significant effects, but of lesser magnitude (40%, 52%, and 57%, respectively; P < 0.001). These results help confirm the chemopreventive activity of NSAIDs against breast cancer and provide the first evidence that a cyclooxygenase 2 blocking agent, celecoxib, possesses strong chemopreventive activity against mammary carcinogenesis.

https://cancerres.aacrjournals.org/content/canres/60/8/2101.full.pdf

Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor.

Epidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade. We conducted a case control study of breast cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 323 incident breast cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 649 cancer free controls matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and breast cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals. Results showed significant risk reductions for selective COX-2 inhibitors as a group (OR = 0.29, 95% CI = 0.14–0.59), regular aspirin (OR = 0.49, 95% CI = 0.26–0.94), and ibuprofen or naproxen (0.36, 95% CI = 0.18–0.72). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of breast cancer. Selective COX-2 inhibitors (celecoxib and rofecoxib) were only recently approved for use in 1999, and rofecoxib (Vioxx) was withdrawn from the marketplace in 2004. Nevertheless, even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71%) reduction in the risk of breast cancer, underscoring their strong potential for breast cancer chemoprevention.

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Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors

Epidemiological and experimental studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the relative risk of human cancer, including breast cancer. Recently, research studies in our laboratories have shown that the selective cyclooxygenase-2 (COX-2) blocker, Celecoxib, given daily in the diet, significantly inhibited the induction of rat mammary tumors by 7,12-dimethylbenz(a) anthracene (DMBA). These studies were extended to evaluate Celecoxib for its effectiveness as an antineoplastic agent in this rat mammary tumor model. We examined the growth inhibitory effects of Celecoxib, given daily in the diet, on the volume and the number of established mammary tumors, vis-a-vis the cancer load (CL). Tumors continued to grow actively in control rats fed chow diet only. In contrast, the Celecoxib-supplemented diet (1500 mg /kg diet) significantly decreased the size of the mammary tumors in rats over the 6 week treatment period, resulting in an average reduction in tumor volume of approximately 32%, relative to the baseline volume (p<0.04). At the end of the 6 week treatment period, average tumor volume was 1.45 cm 3 and 0.13 cm 3 in the control and Celecoxib treated rats respectively. Tumor regression occurred in 90% of the rats. In addition, new tumors continued to emerge in the control group, in contrast to their significantly decreasing numbers in the Celecoxib treated group over the same time period (p<0.05). These results indicate that Celecoxib has significant antineoplastic activity, in addition to its anticarcinogenic effects.

Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model.

Ibuprofen-induced inhibition of cyclooxygenase isoform gene expression and regression of rat mammary carcinomas

We conducted a case control study of selective cyclooxygenase-2 (COX-2) blocking agents and lung cancer. A total of 492 newly diagnosed lung cancer cases were ascertained during January 1, 2002 to September 30, 2004, at The Ohio State University Medical Center, Columbus, Ohio. All cases were confirmed by examination of the pathology report. Healthy population controls without cancer were ascertained during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors (primarily celecoxib or rofecoxib) and nonselective NSAIDs such as ibuprofen and aspirin. Estimates of odds ratios (OR) were obtained with adjustment for cigarette smoking, age and other potential confounders using logistic regression analysis. Odds Ratios for selective COX-2 inhibitors were adjusted for past use of other NSAIDs. Use of any selective COX-2 inhibitor for more than one year produced a significant (60%) reduction in the risk of lung cancer (OR=0.40, 95% CI=0.19-0.81). Observed risk reductions were consistent for men (OR=0.26, 95% CI=0.10-0.62) and women (OR=0.52, 95% CI=0.24-1.13) and for individual COX-2 inhibitors (OR=0.28, 95% CI=-0.12-0.67, for celecoxib and OR=0.55, 95% CI=0.19-1.56, for rofecoxib). Intake of ibuprofen or aspirin also produced significant risk reductions (OR=0.40, 95% CI=0.23-0.73 and OR=0.53, 95% CI=0.34-0.82, respectively), whereas acetaminophen, an analgesic with negligible COX-2 activity, had no effect on the risk (OR=1.36, 95% CI=0.53-3.37). This investigation demonstrates for the first time that selective COX-2 blocking agents have strong potential for the chemoprevention of human lung cancer.

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Galal A. Alshafie

Papers

Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor.

Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors

Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model.

Ibuprofen-induced inhibition of cyclooxygenase isoform gene expression and regression of rat mammary carcinomas

Reduced Risk of Human Lung Cancer by Selective Cyclooxygenase 2 (Cox-2) Blockade: Results of a Case Control Study